@article{MTMT:34300023, title = {Preparation of Phage Antibodies to Heat Shock Proteins and Studying the Dynamics of their Accumulation in Mice with Xenotransplant Tumors}, url = {https://m2.mtmt.hu/api/publication/34300023}, author = {Dykman, L. A. and Staroverov, S. A. and Vyrshchikov, R. D. and Fursova, K. K. and Brovko, F. A. and Soldatov, D. A. and Guliy, O. I.}, doi = {10.1134/S0003683823040051}, journal-iso = {APPL BIOCHEM MICRO+}, journal = {APPLIED BIOCHEMISTRY AND MICROBIOLOGY}, volume = {59}, unique-id = {34300023}, issn = {0003-6838}, abstract = {Using a naive human scFv phage library, affinity selection of miniantibodies specific to heat shock proteins isolated from MH22a hepatoma cells and Sp2/0-Ag14 plasmacytoma cells was carried out. By using the obtained phage antibodies, the dynamics of the concentration of heat shock proteins in the blood sera of mice with implanted MH22a tumors were examined by dot immunoassay and enzyme-linked immunosorbent assay. Starting from the 14th day after xenotransplantation there was a gradual increase in the level of heat shock proteins in the blood serum. It was found that after implantation of tumor cells, tumor growth was accompanied by a significant increase in the accumulation of heat shock proteins in the blood serum. It has been shown that miniantibodies specific to heat shock proteins are an effective tool for determining and monitoring the accumulation of heat shock proteins in the blood serum of animals.}, keywords = {IMMUNOASSAY; Heat shock proteins; Antibody phage library; tumor cell cultures; xenotransplanted tumors}, year = {2023}, eissn = {1608-3024}, pages = {539-545} } @article{MTMT:34620211, title = {Clinical implications of heat shock protein 70 in oral carcinogenesis and prediction of progression and recurrence in oral squamous cell carcinoma patients: a retrospective clinicopathological study}, url = {https://m2.mtmt.hu/api/publication/34620211}, author = {Elhendawy, Heba A.}, doi = {10.1186/s40001-023-01433-8}, journal-iso = {EUR J MED RES}, journal = {EUROPEAN JOURNAL OF MEDICAL RESEARCH}, volume = {28}, unique-id = {34620211}, issn = {0949-2321}, abstract = {BackgroundOral cancer is a common cause of death worldwide. The search for novel biomarkers for oral cancer is an ongoing struggle. Prognostic biomarkers are of great importance in diagnosis, and prediction of the cancer outcome. There are several disagreements in oral cancer studies over the role of heat shock proteins as prognostic markers. The current study investigated HSP70 expression in diverse tissues ranging from normal oral mucosa to dysplastic oral epithelium and oral squamous cell carcinoma to determine its role in oral carcinogenesis. Moreover, HSP70 was evaluated concerning different prognostic parameters to determine its capability in predicting cancer progression. Recurrence of tumor was recorded, and patients` disease-free survival was calculated and analyzed considering HSP70 expression to determine the potential utility of HSP70 immuno-expression in predicting recurrence.MethodsA retrospective study was accomplished on 50 cases of OSCC. Biopsies from the cancerous tissue, the free surgical margin, and the normal oral mucosa were used. The grading of dysplastic epithelium and OSCCs followed the criteria of WHO classification (2017). The clinicopathological and follow-up records for each patient were retrieved. Pearson's Chi-square test, one-way ANOVA, and post hoc tests were used to analyze the variance of HSP70 immuno-expression concerning different parameters. The Kaplan-Meier method was used to compute and visualize disease-free survival, and the log-rank test was used to analyze the data. With Cox regression, univariate and multivariate survival analyses were run. A P-value of 0.05 or less was regarded as statistically significant.ResultsA significant increased expression of HSP70 was observed as the tissue progressed from normal to dysplastic epithelium, and carcinoma (P = 0.000). HSP70 revealed a significant increased expression by progression from mild to severe dysplasia (P = 0.023), and also from well to moderately and poorly differentiated carcinoma (P = 0.000). High HSP70 immuno-expression was significantly associated with progression of OSCC; large-sized tumors (P = 0.002), advanced TNM clinical stages (P = 0.001), positive nodal involvement (P = 0.001), presence of recurrence (P = .008), and reduced DFS (P = 0.014).ConclusionHSP70 has a crucial contribution to oral carcinogenesis, and its immune-expression could potentially be used as predictor of progression and recurrence of OSCC patients.Trial registration: Retrospectively registered.ConclusionHSP70 has a crucial contribution to oral carcinogenesis, and its immune-expression could potentially be used as predictor of progression and recurrence of OSCC patients.Trial registration: Retrospectively registered.}, keywords = {Recurrence; immunohistochemistry; heat shock protein 70; DFS; Oral squamous cell carcinoma; prognostic indicators}, year = {2023}, eissn = {2047-783X} } @article{MTMT:34299816, title = {Heat Shock Proteins in Cancer Diagnostics}, url = {https://m2.mtmt.hu/api/publication/34299816}, author = {Guliy, O. I. and Staroverov, S. A. and Dykman, L. A.}, doi = {10.1134/S0003683823040063}, journal-iso = {APPL BIOCHEM MICRO+}, journal = {APPLIED BIOCHEMISTRY AND MICROBIOLOGY}, volume = {59}, unique-id = {34299816}, issn = {0003-6838}, abstract = {With the growing number of cancer cases, new tools are required to obtain extensive molecular profiles of patients to help identify the disease. Early diagnosis of cancer is based on the analysis of relevant biomarkers, which can be used to monitor the population in order to identify the disease until it can be determined using standard methods and is not clinically manifest. Heat shock proteins, which act as molecular chaperones, are among the potential markers of cancer. Changes in heat shock protein expression can serve as an important diagnostic marker of the cell's response to damage. This paper presents a brief overview of the prevalence of oncological diseases in the world, the need for the development of early oncological diagnostics, as well as the prospects for the use of heat shock proteins in making an oncological diagnosis.}, keywords = {Overexpression; cancer diagnostics; Heat shock proteins; chaperones; Tumor markers}, year = {2023}, eissn = {1608-3024}, pages = {395-407} } @article{MTMT:34521706, title = {Biomarkers in Adult-Type Diffuse Gliomas: Elevated Levels of Circulating Vesicular Heat Shock Protein 70 Serve as a Biomarker in Grade 4 Glioblastoma and Increase NK Cell Frequencies in Grade 3 Glioma}, url = {https://m2.mtmt.hu/api/publication/34521706}, author = {Lennartz, P. and Thölke, D. and Bashiri, Dezfouli A. and Pilz, M. and Lobinger, D. and Messner, V. and Zanth, H. and Ainslie, K. and Kafshgari, M.H. and Rammes, G. and Ballmann, M. and Schlegel, M. and Foulds, G.A. and Pockley, A.G. and Schmidt-Graf, F. and Multhoff, G.}, doi = {10.3390/biomedicines11123235}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {11}, unique-id = {34521706}, year = {2023}, eissn = {2227-9059} } @article{MTMT:34268838, title = {The Role of Extracellular Heat Shock Proteins in Cardiovascular Diseases}, url = {https://m2.mtmt.hu/api/publication/34268838}, author = {Patnaik, Soumya and Nathan, Sriram and Kar, Biswajit and Gregoric, Igor D. and Li, Yi-Ping}, doi = {10.3390/biomedicines11061557}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {11}, unique-id = {34268838}, abstract = {In the early 1960s, heat shock proteins (HSPs) were first identified as vital intracellular proteinaceous components that help in stress physiology and reprogram the cellular responses to enable the organism's survival. By the early 1990s, HSPs were detected in extracellular spaces and found to activate gamma-delta T-lymphocytes. Subsequent investigations identified their association with varied disease conditions, including autoimmune disorders, diabetes, cancer, hepatic, pancreatic, and renal disorders, and cachexia. In cardiology, extracellular HSPs play a definite, but still unclear, role in atherosclerosis, acute coronary syndromes, and heart failure. The possibility of HSP-targeted novel molecular therapeutics has generated much interest and hope in recent years. In this review, we discuss the role of Extracellular Heat Shock Proteins (Ec-HSPs) in various disease states, with a particular focus on cardiovascular diseases.}, keywords = {APOPTOSIS; ATHEROSCLEROSIS; STRESS; heart failure; Ischemia-reperfusion injury; Heat shock proteins; immune cell activation}, year = {2023}, eissn = {2227-9059} } @article{MTMT:34264040, title = {Circulating Hsp70 Levels and the Immunophenotype of Peripheral Blood Lymphocytes as Potential Biomarkers for Advanced Lung Cancer and Therapy Failure after Surgery}, url = {https://m2.mtmt.hu/api/publication/34264040}, author = {Safi, Seyer and Messner, Luis and Kliebisch, Merten and Eggert, Linn and Ceylangil, Ceyra and Lennartz, Philipp and Jefferies, Benedict and Klein, Henriette and Schirren, Moritz and Dommasch, Michael and Lobinger, Dominik and Multhoff, Gabriele}, doi = {10.3390/biom13050874}, journal-iso = {BIOMOLECULES}, journal = {BIOMOLECULES}, volume = {13}, unique-id = {34264040}, issn = {2218-273X}, abstract = {Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 levels were measured using ELISA, and the immunophenotype of the peripheral blood lymphocytes were measured using multiparameter flow cytometry, to identify a predictive biomarker signature for lung cancer patients pre- and post-operatively, in patients with lung metastases and in patients with COPD as an inflammatory lung disease. The lowest Hsp70 concentrations were found in the healthy controls followed by the patients with advanced COPD. Hsp70 levels sequentially increased with an advancing tumor stage and metastatic disease. In the early-recurrence patients, Hsp70 levels started to increase within the first three months after surgery, but remained unaltered in the recurrence-free patients. An early recurrence was associated with a significant drop in B cells and an increase in Tregs, whereas the recurrence-free patients had elevated T and NK cell levels. We conclude that circulating Hsp70 concentrations might have the potential to distinguish lung cancer from metastatic disease, and might be able to predict an advanced tumor stage and early recurrence in lung cancer patients. Further studies with larger patient cohorts and longer follow-up periods are needed to validate Hsp70 and immunophenotypic profiles as predictive biomarker signatures.}, keywords = {surgery; lung cancer; biomarker; Early recurrence; advanced COPD; circulating Hsp70; immunophenotypic profile}, year = {2023}, eissn = {2218-273X}, orcid-numbers = {Safi, Seyer/0000-0002-2335-4309; Kliebisch, Merten/0009-0000-9090-8482; Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:34114833, title = {The multifunction of HSP70 in cancer: Guardian or traitor to the survival of tumor cells and the next potential therapeutic target}, url = {https://m2.mtmt.hu/api/publication/34114833}, author = {Sha, G. and Jiang, Z. and Zhang, W. and Jiang, C. and Wang, D. and Tang, D.}, doi = {10.1016/j.intimp.2023.110492}, journal-iso = {INT IMMUNOPHARMACOL}, journal = {INTERNATIONAL IMMUNOPHARMACOLOGY}, volume = {122}, unique-id = {34114833}, issn = {1567-5769}, abstract = {Heat shock protein 70 (HSP70) is a highly conserved protein composed of nucleotide-binding domains (NBD) and C-terminal substrate binding domain (SBD) that can function as a “molecular chaperone”. HSP70 was discovered to directly or indirectly play a regulatory role in both internal and external apoptosis pathways. Studies have shown that HSP70 can not only promote tumor progression, enhance tumor cell resistance and inhibit anticancer effects but also induce an anticancer response by activating immune cells. In addition, chemotherapy, radiotherapy and immunotherapy for cancer may be affected by HSP70, which has shown promising potential as an anticancer drug. In this review, we summarized the molecular structure and mechanism of HSP70 and discussed the dual effects of HSP70 on tumor cells and the possibility and potential methods of using HSP70 as a target to treat cancer. © 2023 Elsevier B.V.}, keywords = {APOPTOSIS; CANCER; signal transduction; ANTIBODY; ANGIOGENESIS; METASTASIS; review; human; Cell Survival; Software; Protein Transport; innate immunity; nonhuman; immune system; Protein Conformation; PROTEIN FUNCTION; unclassified drug; immunocompetent cell; antineoplastic agent; Immunogenicity; heat shock protein; Hsp70; cancer therapy; cancer growth; ANTINEOPLASTIC ACTIVITY; heat shock protein 90; heat shock protein 70; ADAPTIVE IMMUNITY; cancer resistance; protein structure; antigen presenting cell; Chaperonin 60; protein interaction; chaperone; cancer cell; Cell Aging; clinical trial (topic); heat shock transcription factor 1; heat shock protein 27; malignant neoplasm; Protein Data Bank; liquid biopsy; heat shock protein 40; versatility; Heat shock protein 70 inhibitor; Immunological therapy; heat shock protein 70 antibody}, year = {2023}, eissn = {1878-1705} } @article{MTMT:34620210, title = {Roles of tissue-resident immune cells in immunotherapy of non-small cell lung cancer}, url = {https://m2.mtmt.hu/api/publication/34620210}, author = {Tang, Rui and Wang, Haitao and Tang, Mingxi}, doi = {10.3389/fimmu.2023.1332814}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {14}, unique-id = {34620210}, issn = {1664-3224}, abstract = {Non-small cell lung cancer (NSCLC) is the most common and lethal type of lung cancer, with limited treatment options and poor prognosis. Immunotherapy offers hope for improving the survival and quality of life of NSCLC patients, but its efficacy depends on the tumor immune microenvironment (TME). Tissue-resident immune cells are a subset of immune cells that reside in various tissues and organs, and play an important role in fighting tumors. In NSCLC, tissue-resident immune cells are heterogeneous in their distribution, phenotype, and function, and can either promote or inhibit tumor progression and response to immunotherapy. In this review, we summarize the current understanding on the characteristics, interactions, and roles of tissue-resident immune cells in NSCLC. We also discuss the potential applications of tissue-resident immune cells in NSCLC immunotherapy, including immune checkpoint inhibitors (ICIs), other immunomodulatory agents, and personalized cell-based therapies. We highlight the challenges and opportunities for developing targeted therapies for tissue-resident immune cells and optimizing existing immunotherapeutic approaches for NSCLC patients. We propose that tissue-resident immune cells are a key determinant of NSCLC outcome and immunotherapy response, and warrant further investigation in future research.}, keywords = {immunotherapy; non-small cell lung cancer; immune checkpoint inhibitors; Tumor immune microenvironment; tissue-resident immune cells}, year = {2023}, eissn = {1664-3224} } @article{MTMT:34559267, title = {Protocol of the HISTOTHERM study: assessing the response to hyperthermia and hypofractionated radiotherapy in recurrent breast cancer}, url = {https://m2.mtmt.hu/api/publication/34559267}, author = {Thomsen, Andreas R. and Sahlmann, Joerg and Bronsert, Peter and Schilling, Oliver and Poensgen, Felicia and May, Annette M. and Timme-Bronsert, Sylvia and Grosu, Anca-Ligia and Vaupel, Peter and Gebbers, Jan-Olaf and Multhoff, Gabriele and Luechtenborg, Anne-Marie}, doi = {10.3389/fonc.2023.1275222}, journal-iso = {FRONT ONCOL}, journal = {FRONTIERS IN ONCOLOGY}, volume = {13}, unique-id = {34559267}, issn = {2234-943X}, abstract = {Introduction Breast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43 degrees C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.Methods and analyses Patients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43 degrees C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.Registration The study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).}, keywords = {PLASMA-MEMBRANE; SURVIVAL; methodology; Prognosis; Therapy; Hsp70; breast cancer; HYPERTHERMIA; longitudinal study; Regression; LOCAL RECURRENCE; Predictive markers; CIRCULATING TUMOR-CELLS; Hypofractionated radiotherapy; reirradiation; Recurrent breast cancer}, year = {2023}, eissn = {2234-943X} } @article{MTMT:34261955, title = {Hsp70-A Universal Biomarker for Predicting Therapeutic Failure in Human Female Cancers and a Target for CTC Isolation in Advanced Cancers}, url = {https://m2.mtmt.hu/api/publication/34261955}, author = {Xanthopoulos, Alexia and Samt, Ann-Kathrin and Guder, Christiane and Taylor, Nicholas and Roberts, Erika and Herf, Hannah and Messner, Verena and Trill, Anskar and Holzmann, Katharina Larissa Kreszentia and Kiechle, Marion and Seifert-Klauss, Vanadin and Zschaeck, Sebastian and Schatka, Imke and Tauber, Robert and Schmidt, Robert and Enste, Katrin and Pockley, Alan Graham and Lobinger, Dominik and Multhoff, Gabriele}, doi = {10.3390/biomedicines11082276}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {11}, unique-id = {34261955}, abstract = {Heat shock protein 70 (Hsp70) is frequently overexpressed in many different tumor types. However, Hsp70 has also been shown to be selectively presented on the plasma membrane of tumor cells, but not normal cells, and this membrane form of Hsp70 (mHsp70) could be considered a universal tumor biomarker. Since viable, mHsp70-positive tumor cells actively release Hsp70 in lipid micro-vesicles, we investigated the utility of Hsp70 in circulation as a universal tumor biomarker and its potential as an early predictive marker of therapeutic failure. We have also evaluated mHsp70 as a target for the isolation and enumeration of circulating tumor cells (CTCs) in patients with different tumor entities. Circulating vesicular Hsp70 levels were measured in the peripheral blood of tumor patients with the compHsp70 ELISA. CTCs were isolated using cmHsp70.1 and EpCAM monoclonal antibody (mAb)-based bead approaches and characterized by immunohistochemistry using cytokeratin and CD45-specific antibodies. In two out of 35 patients exhibiting therapeutic failure two years after initial diagnosis of non-metastatic breast cancer, progressively increasing levels of circulating Hsp70 had already been observed during therapy, whereas levels in patients without subsequent recurrence remained unaltered. With regards to CTC isolation from patients with different tumors, an Hsp70 mAb-based selection system appears superior to an EpCAM mAb-based approach. Extracellular and mHsp70 can therefore serve as a predictive biomarker for therapeutic failure in early-stage tumors and as a target for the isolation of CTCs in various tumor diseases.}, keywords = {Hsp70; lung cancer; breast cancer; Prostate cancer; Head and neck cancer; ENDOMETRIAL CANCER; liquid biopsy; tumor biomarker; Circulating tumor cells}, year = {2023}, eissn = {2227-9059}, orcid-numbers = {Schatka, Imke/0000-0002-2628-6145; Pockley, Alan Graham/0000-0001-9593-6431; Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:33406474, title = {Impaired Heat Shock Protein Expression in Activated T Cells in B-Cell Lymphoma}, url = {https://m2.mtmt.hu/api/publication/33406474}, author = {Albakova, Zarema and Mangasarova, Yana and Sapozhnikov, Alexander}, doi = {10.3390/biomedicines10112747}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {10}, unique-id = {33406474}, abstract = {Heat shock proteins (HSPs) are molecular chaperones that act in a variety of cellular processes, ensuring protein homeostasis and integrity. HSPs play critical roles in the modulation of various immune cells. However, the role of HSPs in T cell activation is largely unknown. We show that HSPs are upregulated following CD3/CD28 stimulation, suggesting that HSP expression might be regulated via TCR. We found that B-cell lymphoma (BCL) patients have dysregulated expression of intracellular and extracellular HSPs, immune checkpoints PD-1, CTLA-4, and STAT3 in CD3/CD28-activated T cells. Consistent with previous findings, we show that HSP90 inhibition downregulated CD4 and CD8 surface markers in healthy controls and BCL patients. HSP90 inhibition alone or in combination with PD-1 or CTLA-4 inhibitors differentially affected CD4+ and CD8+ T cell degranulation responses when stimulated with allogeneic DCs or CD3/CD28 in BCL patients. Additionally, we showed that HSP90 inhibition does not significantly affect intracellular PD-1 and CTLA-4 expression in CD3/CD28-activated T cells. These findings may provide the basis for the discovery of novel immunological targets for the treatment of cancer patients and improve our understanding of HSP functions in immune cells.}, keywords = {Hsp60; T cells; Hsp70; LYMPHOMA; HSP90; Heat shock proteins; extracellular HSPs}, year = {2022}, eissn = {2227-9059} } @article{MTMT:33322615, title = {The circulating 70 kDa heat shock protein (HSPA1A) level is a potential biomarker for breast carcinoma and its progression}, url = {https://m2.mtmt.hu/api/publication/33322615}, author = {de Freitas, Gabriela Boufelli and Penteado, Laura and Miranda, Mila Meneguelli and Filassi, Jose Roberto and Baracat, Edmund Chada and Linhares, Iara Moreno}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {12}, unique-id = {33322615}, issn = {2045-2322}, abstract = {The early diagnosis of breast cancer can improve treatment and prognosis. We sought to evaluate whether the serum concentration of the 70 kDa heat shock protein (HSPA1A) was elevated in Brazilian women with breast cancer, and if levels correlated with tumor characteristics. This was a cross-sectional, analytical, case-control exploratory study performed at The University of Sao Paulo School of Medicine. From September 2017 to December 2018, 68 women with breast cancer and 59 controls were recruited. The HSPA1A concentration in serum samples was determined by ELISA by individuals blinded to the clinical data. The mean ages in the study and control groups were 54.9 and 52.0 years, respectively. The median serum levels of HSPA1A were elevated in women with breast cancer (1037 pg/ml) compared with controls (300 pg/ml) (p < 0.001). Elevated HSPA1A levels were associated with advanced histological tumor grade (p < 0.001) and with the cell proliferation index (KI67) (p = 0.0418). The HSPA1A concentration was similar in women with different histological subtypes, nuclear grade, hormone receptor expression, HER2 status and the presence or absence of angiolymphatic invasion. Elevated serum HSPA1A in Brazilian women with advanced histological grade and proliferation index breast cancer supports the potential value of additional investigation on larger and more varied populations to verify the value of HSPA1A detection as a component of breast cancer diagnosis and progression.}, year = {2022}, eissn = {2045-2322}, pages = {13012-13020} } @article{MTMT:32527577, title = {Ameliorating cancer cachexia by inhibiting cancer cell release of Hsp70 and Hsp90 with omeprazole}, url = {https://m2.mtmt.hu/api/publication/32527577}, author = {Liu, Z. and Xiong, J. and Gao, S. and Zhu, M.X. and Sun, K. and Li, M. and Zhang, G. and Li, Y.-P.}, doi = {10.1002/jcsm.12851}, journal-iso = {J CACHEXIA SARCOPENIA MUSCLE}, journal = {JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE}, volume = {13}, unique-id = {32527577}, issn = {2190-5991}, year = {2022}, eissn = {2190-6009}, pages = {636-647} } @article{MTMT:33322613, title = {Elevated circulating Hsp70 levels are correlative for malignancies in different mammalian species}, url = {https://m2.mtmt.hu/api/publication/33322613}, author = {Lukas, Salvermoser and Flisikowski, Krzysztof and Dressel-Bohm, Susann and Nytko, Katarzyna J. and Bley, Carla Rohrer and Schnieke, Angelika and Samt, Ann-Kathrin and Thoelke, Dennis and Lennartz, Philipp and Schwab, Melissa and Wang, Fei and Dezfouli, Ali Bashiri and Multhoff, Gabriele}, doi = {10.1007/s12192-022-01311-y}, journal-iso = {CELL STRESS CHAPERON}, journal = {CELL STRESS & CHAPERONES}, unique-id = {33322613}, issn = {1355-8145}, abstract = {Circulating Hsp70 levels were determined in feline and porcine cohorts using two different ELISA systems. These comparative animal models of larger organisms often reflect diseases, and especially malignant tumors, better than conventional rodent models. It is therefore essential to investigate the biology and utility of tumor biomarkers in animals such as cats and pigs. In this study, levels of free Hsp70 in the blood of cats with spontaneously occurring tumors were detected using a commercial Hsp70 ELISA (R&D Systems). Sub-analysis of different tumor groups revealed that animals with tumors of epithelial origin presented with significantly elevated circulating Hsp70 concentrations. In addition to free Hsp70 levels measured with the R&D Systems Hsp70 ELISA, levels of exosomal Hsp70 were determined using the compHsp70 ELISA in pigs. Both ELISA systems detected significantly elevated Hsp70 levels (R&D Systems: median 24.9 ng/mL; compHsp70: median 44.2 ng/mL) in the blood of a cohort of APC(1311/+) pigs diagnosed with high-grade adenoma polyps, and the R&D Systems Hsp70 ELISA detected also elevated Hsp70 levels in animals with low-grade polyps. In contrast, in flTP53(R167H) pigs, suffering from malignant osteosarcoma, the compHsp70 ELISA (median 674.32 ng/mL), but not the R&D Systems Hsp70 ELISA (median 4.78 ng/mL), determined significantly elevated Hsp70 concentrations, indicating that in tumor-bearing animals, the dominant form of Hsp70 is of exosomal origin. Our data suggest that both ELISA systems are suitable for detecting free circulating Hsp70 levels in pigs with high-grade adenoma, but only the compHsp70 ELISA can measure elevated, tumor-derived exosomal Hsp70 levels in tumor-bearing animals.}, keywords = {Osteosarcoma; Colorectal polyps; tumor biomarker; EXTRACELLULAR HSP70; CompHsp70 ELISA; Tumor animal model}, year = {2022}, eissn = {1466-1268} } @article{MTMT:32479100, title = {Heat shock proteins and exosomes in cancer theranostics}, url = {https://m2.mtmt.hu/api/publication/32479100}, author = {Regimbeau, M. and Abrey, J. and Vautrot, V. and Causse, S. and Gobbo, J. and Garrido, C.}, doi = {10.1016/j.semcancer.2021.07.014}, journal-iso = {SEMIN CANCER BIOL}, journal = {SEMINARS IN CANCER BIOLOGY}, volume = {86}, unique-id = {32479100}, issn = {1044-579X}, abstract = {Heat shock proteins (HSPs) are a superfamily of molecular chaperones that were discovered through their ability to be induced by different stresses including heat shock. Other than their function as chaperones in proteins homeostasis, HSPs have been shown to inhibit different forms of cell death and to participate in cell proliferation and differentiation processes. Because cancer cells have to rewire their metabolism, they require a high amount of these stress-inducible chaperones for their survival. Therefore, HSPs are unusually abundant in cancer cells where they have oncogene-like functions. In cancer, HSPs have been involved in the regulation of apoptosis, immune responses, angiogenesis, metastasis and treatment resistance. Recently, HSPs have been shown to be secreted through exosomes by cancer cells. These tumor-derived exosomes can be used as circulating markers: HSP-exosomes have been reported as biomarkers of cancer dissemination, response to therapy and/or patient outcome. A new range of functions, mostly in modulation of anticancer immune responses, have been described for these extracellular HSPs. In this review, we will describe those recently reported functions of HSP-exosomes that makes them both targets for anticancer therapeutics and biomarkers for the monitoring of the disease. We will also discuss their emerging interest in cancer vaccines. © 2021 Elsevier Ltd}, keywords = {cancer therapy; Heat shock proteins; Cancer Vaccines; Exosomes; circulating biomarkers}, year = {2022}, eissn = {1096-3650}, pages = {46-57} } @article{MTMT:32646078, title = {Redox modulation by plant polyphenols targeting vitagenes for chemoprevention and therapy: Relevance to novel anti-cancer interventions and mini-brain organoid technology}, url = {https://m2.mtmt.hu/api/publication/32646078}, author = {Scuto, Maria and Ontario, Maria Laura and Salinaro, Angela Trovato and Caligiuri, Isabella and Rampulla, Francesco and Zimbone, Vincenzo and Modafferi, Sergio and Rizzolio, Flavio and Canzonieri, Vincenzo and Calabrese, Edward J. and Calabrese, Vittorio}, doi = {10.1016/j.freeradbiomed.2021.12.267}, journal-iso = {FREE RADICAL BIO MED}, journal = {FREE RADICAL BIOLOGY AND MEDICINE}, volume = {179}, unique-id = {32646078}, issn = {0891-5849}, abstract = {The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer.}, keywords = {STEM-CELLS; SIGNALING PATHWAYS; INDUCED APOPTOSIS; NANOPARTICLES; polyphenols; HEAT-SHOCK PROTEINS; Hormesis; Brain tumors; Chemoprevention; Biochemistry & Molecular Biology; Mediterranean diet; vitagenes; COLORECTAL-CANCER CELLS; Oxidative stress; HEME OXYGENASE-1 EXPRESSION; ENDOTHELIAL-CELL MIGRATION; REDUCES IN-VITRO}, year = {2022}, eissn = {1873-4596}, pages = {59-75}, orcid-numbers = {Caligiuri, Isabella/0000-0002-4355-5597} } @article{MTMT:33322612, title = {Elevated Levels of Circulating Hsp70 and an Increased Prevalence of CD94+/CD69+NK Cells Is Predictive for Advanced Stage Non-Small Cell Lung Cancer}, url = {https://m2.mtmt.hu/api/publication/33322612}, author = {Seier, Sophie and Dezfouli, Ali Bashiri and Lennartz, Philipp and Pockley, Alan Graham and Klein, Henriette and Multhoff, Gabriele}, doi = {10.3390/cancers14225701}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {14}, unique-id = {33322612}, abstract = {Simple Summary This study reveals that circulating Hsp70 levels could serve as a tumor biomarker for patients with NSCLC in advanced UICC stages. All patients in advanced tumor stages had significantly elevated Hsp70 levels in the circulation compared to a healthy control cohort and an early-stage tumor cohort, and Hsp70 levels progressively increased with higher UICC tumor stages. These findings demonstrate the potential of Hsp70 measurements to predict an advanced tumor stage in NSCLC patients. We have also demonstrated that the prevalence of CD3-/CD94+ NK cells and CD8+ cytotoxic T cells were greater in advanced tumor stages, whereas that of CD4+ T helper cells was decreased. We hypothesize that raised levels of circulating Hsp70 in higher tumor stages might support NK cell proliferation, but that a lowered prevalence of CD4+ T helper cells could temper the capacity of cytolytic CD8+ T cells and NK cells to control tumor growth. Non-small cell lung cancer (NSCLC) is the second most frequently diagnosed tumor worldwide. Despite the clinical progress which has been achieved by multimodal therapies, including radiochemotherapy, and immune checkpoint inhibitor blockade, the overall survival of patients with advanced-stage NSCLC remains poor, with less than 16 months. It is well established that many aggressive tumor entities, including NSCLC, overexpress the major stress-inducible heat shock protein 70 (Hsp70) in the cytosol, present it on the plasma membrane in a tumor-specific manner, and release Hsp70 into circulation. Although high Hsp70 levels are associated with tumor aggressiveness and therapy resistance, membrane-bound Hsp70 can serve as a tumor-specific antigen for Hsp70-primed natural killer (NK) cells, expressing the C-type lectin receptor CD94, which is part of the activator receptor complex CD94/NKG2C. Therefore, we investigated circulating Hsp70 levels and changes in the composition of peripheral blood lymphocyte subsets as potential biomarkers for the advanced Union for International Cancer Control (UICC) stages in NSCLC. As expected, circulating Hsp70 levels were significantly higher in NSCLC patients compared to the healthy controls, as well as in patients with advanced UICC stages compared to those in UICC stage I. Smoking status did not influence the circulating Hsp70 levels significantly. Concomitantly, the proportions of CD4+ T helper cells were lower compared to the healthy controls and stage I tumor patients, whereas that of CD8+ cytotoxic T cells was progressively higher. The prevalence of CD3-/CD56+, CD3-/NKp30, CD3-/NKp46+, and CD3-/NKG2D+ NK cells was higher in stage IV/IIIB of the disease than in stage IIIA but were not statistically different from that in healthy individuals. However, the proportion of NK cells expressing CD94 and the activation/exhaustion marker CD69 significantly increased in higher tumor stages compared with stage I and the healthy controls. We speculate that although elevated circulating Hsp70 levels might promote the prevalence of CD94+ NK cells in patients with advanced-stage NSCLC, the cytolytic activity of these NK cells also failed to control tumor growth due to insufficient support by pro-inflammatory cytokines from CD4+ T helper cells. This hypothesis is supported by a comparative multiplex cytokine analysis of the blood in lung cancer patients with a low proportion of CD4+ T cells, a high proportion of NK cells, and high Hsp70 levels versus patients with a high proportion of CD4+ T cells exhibiting lower IL-2, IL-4, IL-6, IFN-gamma, granzyme B levels.}, keywords = {liquid biopsy; tumor biomarker; non-small-cell lung cancer (NSCLC); circulating heat-shock protein 70; UICC stage; CD4+T cell drop}, year = {2022}, eissn = {2072-6694}, orcid-numbers = {Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:31804437, title = {Extracellular heat shock proteins and cancer: New perspectives}, url = {https://m2.mtmt.hu/api/publication/31804437}, author = {Albakova, Z. and Siam, M.K.S. and Sacitharan, P.K. and Ziganshin, R.H. and Ryazantsev, D.Y. and Sapozhnikov, A.M.}, doi = {10.1016/j.tranon.2020.100995}, journal-iso = {TRANSL ONCOL}, journal = {TRANSLATIONAL ONCOLOGY}, volume = {14}, unique-id = {31804437}, issn = {1944-7124}, year = {2021}, eissn = {1936-5233} } @article{MTMT:31968861, title = {Heat Shock Proteins in Lymphoma Immunotherapy.}, url = {https://m2.mtmt.hu/api/publication/31968861}, author = {Albakova, Zarema and Mangasarova, Yana and Sapozhnikov, Alexander}, doi = {10.3389/fimmu.2021.660085}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {12}, unique-id = {31968861}, issn = {1664-3224}, abstract = {Immunotherapy harnessing the host immune system for tumor destruction revolutionized oncology research and advanced treatment strategies for lymphoma patients. Lymphoma is a heterogeneous group of cancer, where the central roles in pathogenesis play immune evasion and dysregulation of multiple signaling pathways. Immunotherapy-based approaches such as engineered T cells (CAR T), immune checkpoint modulators and NK cell-based therapies are now in the frontline of lymphoma research. Even though emerging immunotherapies showed promising results in treating lymphoma patients, low efficacy and on-target/off-tumor toxicity are of a major concern. To address that issue it is suggested to look into the emerging role of heat shock proteins. Heat shock proteins (HSPs) showed to be highly expressed in lymphoma cells. HSPs are known for their abilities to modulate immune responses and inhibit apoptosis, which made their successful entry into cancer clinical trials. Here, we explore the role of HSPs in Hodgkin and Non-Hodgkin lymphoma and their involvement in CAR T therapy, checkpoint blockade and NK cell- based therapies. Understanding the role of HSPs in lymphoma pathogenesis and the ways how HSPs may enhance anti-tumor responses, may help in the development of more effective, specific and safe immunotherapy.}, keywords = {LYMPHOMA; Heat shock proteins; checkpoint inhibitors; CAR T; CAR NK}, year = {2021}, eissn = {1664-3224} } @article{MTMT:32149594, title = {The role of heat shock proteins in neoplastic processes and the research on their importance in the diagnosis and treatment of cancer}, url = {https://m2.mtmt.hu/api/publication/32149594}, author = {Boliukh, I. and Rombel-Bryzek, A. and Żuk, O. and Radecka, B.}, doi = {10.5114/wo.2021.106006}, journal-iso = {WSPOLCZESNA ONKOL}, journal = {WSPOLCZESNA ONKOLOGIA}, volume = {25}, unique-id = {32149594}, issn = {1428-2526}, abstract = {Heat shock proteins (HSPs) are chaperones with highly conservative primary structure, necessary in the processes of protein folding to the most energetically advantageous conformation and maintaining their stability. HSPs perform a number of important functions in various cellular processes and are capable of modulating pathophysiological conditions at the cellular and systemic levels. An example is the high level of HSP expression in neoplastic tissues, which disrupts the apoptosis of transformed cells and promotes the processes of proliferation, invasion, and metastasis. In addition, an increasing amount of information is appearing about the participation of HSPs in the formation of multidrug resistance. This paper provides a review of the current state of research on the fundamental importance as well as the diagnostic and prognostic role of various classes of HSP in cancer treatment. It presents the prospects for using HSPs as biological markers of disease progression and targets in various cancer treatment strategies. However, the need for additional research is quite high. Only numerous joint efforts of research groups will allow the effective use of HSPs as a tool to combat cancer. © 2021 Termedia Publishing House Ltd.. All rights reserved.}, keywords = {APOPTOSIS; APOPTOSIS; CANCER; METASTASIS; review; human; amino acid sequence; nonhuman; cell proliferation; biological marker; Protein Folding; Protein Conformation; Protein Stability; disease exacerbation; protein expression; heat shock protein; multidrug resistance; biological activity; cancer therapy; cancer diagnosis; heat shock protein 90; heat shock protein 70; Heat shock proteins; cancer research; tumor cell; cell invasion; molecularly targeted therapy; heat shock protein 27; cancer prognosis; anti-cancer therapy; oncogenesis and malignant transformation; transformed cell}, year = {2021}, eissn = {1897-4309}, pages = {73-79} } @article{MTMT:32373004, title = {Heat Shock Proteins 27, 70, and 110: Expression and Prognostic Significance in Colorectal Cancer}, url = {https://m2.mtmt.hu/api/publication/32373004}, author = {Hrudka, Jan and Jelinkova, Karolina and Fiserova, Hana and Matej, Radoslav and Mandys, Vaclav and Waldauf, Petr}, doi = {10.3390/cancers13174407}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32373004}, abstract = {Simple Summary Heat shock proteins (HSPs) are cytoprotective chaperones occurring in virtually all living organisms including various types of cancer cells to repair proteotoxic damage. Some of HSPs influence tumor prognosis and represent promising therapeutic targets. To clarify prognostic significance of HSPs 27, 70, and 110 in colorectal carcinoma, we retrospectively performed HSP immunohistochemistry on tissue microarrays from archive tumor tissue from 297 patients. Survival analysis revealed significantly shorter overall survival (OS) and borderline insignificantly shorter cancer specific survival (CSS) in patients with HSP70+ tumors. In HSP27+, both OS and CSS were insignificantly shorter. HSP110 showed no influence on survival. We found an association of HSP27 and HSP70 expression with advanced cancer stage. In multivariate analysis, only advanced stage and right sided localization were independent predictors of worse survival, whereas all three examined HSPs were insignificant. In conclusion, from all three HSPs examined in our study, only HSP70 had an impact on colorectal cancer prognosis, although it is stage-dependent. Heat shock proteins (HSPs) are evolutionarily conserved chaperones occurring in virtually all living organisms playing a key role in the maintenance of cellular homeostasis. They are constitutively expressed to prevent and repair protein damage following various physiological and environmental stressors. HSPs are overexpressed in various types of cancers to provide cytoprotective function, and they have been described to influence prognosis and response to therapy. Moreover, they have been used as a tumor marker in blood serum biochemistry and they represent a potentially promising therapeutic target. To clarify prognostic significance of two canonical HSPs (27 and 70) and less known HSP110 (previously known as HSP105) in colorectal carcinoma (CRC), we retrospectively performed HSP immunohistochemistry on tissue microarrays from formalin-fixed paraffin-embedded tumor tissue from 297 patients with known follow-up. Survival analysis (univariate Kaplan-Meier analysis with the log-rank test and multivariate Cox regression) revealed significantly shorter overall survival (OS, mean 5.54 vs. 7.07, p = 0.033) and borderline insignificantly shorter cancer specific survival (CSS, mean 6.3 vs. 7.87 years, p = 0.066) in patients with HSP70+ tumors. In the case of HSP27+ tumors, there was an insignificantly shorter OS (mean 6.36 vs. 7.13 years, p = 0.2) and CSS (mean 7.17 vs. 7.95 years, p = 0.2). HSP110 showed no significant impact on survival. Using Pearson's chi-squared test, there was a significant association of HSP27 and HSP70 expression with advanced cancer stage. HSP27+ tumors were more frequently mismatch-repair proficient and vice versa (p = 0.014), and they occurred more often in female patients and vice versa (p = 0.015). There was an enrichment of left sided tumors with HSP110+ compared to the right sided (p = 0.022). In multivariate Cox regression adjusted on the UICC stage, grade and right/left side; both HSPs 27 and 70 were not independent survival predictors (p = 0.616 & p = 0.586). In multivariate analysis, only advanced UICC stage (p = 0) and right sided localization (p = 0.04) were independent predictors of worse CSS. In conclusion, from all three HSPs examined in our study, only HSP70 expression worsened CRC prognosis, although stage-dependent. The contribution of this article may be seen as a large survival analysis of HSPs 27 and 70 and the largest analysis of HSP110 described in CRC.}, keywords = {SURVIVAL; Prognosis; heat shock protein; Hsp70; colorectal carcinoma; Hsp27; Hsp110}, year = {2021}, eissn = {2072-6694}, orcid-numbers = {Hrudka, Jan/0000-0002-5649-4586; Matej, Radoslav/0000-0002-6152-6343; Waldauf, Petr/0000-0003-4668-5837} } @article{MTMT:32373007, title = {Potential Role of Hsp70 and Activated NK Cells for Prediction of Prognosis in Glioblastoma Patients}, url = {https://m2.mtmt.hu/api/publication/32373007}, author = {Lobinger, Dominik and Gempt, Jens and Sievert, Wolfgang and Barz, Melanie and Schmitt, Sven and Nguyen, Huyen Thie and Stangl, Stefan and Werner, Caroline and Wang, Fei and Wu, Zhiyuan and Fan, Hengyi and Zanth, Hannah and Shevtsov, Maxim and Pilz, Mathias and Riederer, Isabelle and Schwab, Melissa and Schlegel, Juergen and Multhoff, Gabriele}, doi = {10.3389/fmolb.2021.669366}, journal-iso = {FRONT MOL BIOSCI}, journal = {FRONTIERS IN MOLECULAR BIOSCIENCES}, volume = {8}, unique-id = {32373007}, abstract = {Despite rapid progress in the treatment of many cancers, glioblastoma remains a devastating disease with dismal prognosis. The aim of this study was to identify chaperone- and immune-related biomarkers to improve prediction of outcome in glioblastoma. Depending on its intra- or extracellular localization the major stress-inducible heat shock protein 70 (Hsp70) fulfills different tasks. In the cytosol Hsp70 interferes with pro-apoptotic signaling pathways and thereby protects tumor cells from programmed cell death. Extracellular Hsp70 together with pro-inflammatory cytokines are reported to stimulate the expression of activatory NK cell receptors, recognizing highly aggressive human tumor cells that present Hsp70 on their cell surface. Therefore, intra-, extracellular and membrane-bound Hsp70 levels were assessed in gliomas together with activatory NK cell receptors. All gliomas were found to be membrane Hsp70-positive and high grade gliomas more frequently show an overexpression of Hsp70 in the nucleus and cytosol. Significantly elevated extracellular Hsp70 levels are detected in glioblastomas with large necrotic areas. Overall survival (OS) is more favorable in patients with low Hsp70 serum levels indicating that a high Hsp70 expression is associated with an unfavorable prognosis. The data provide a first hint that elevated frequencies of activated NK cells at diagnosis might be associated with a better clinical outcome.}, keywords = {Hsp70; biomarker; NK cells; glioblastoma; tumor immunology; predcition of prognosis}, year = {2021}, eissn = {2296-889X}, orcid-numbers = {Shevtsov, Maxim/0000-0002-8539-2239; Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:32373006, title = {Extracellular Heat Shock Proteins as Therapeutic Targets and Biomarkers in Fibrosing Interstitial Lung Diseases}, url = {https://m2.mtmt.hu/api/publication/32373006}, author = {Tanguy, Julie and Pommerolle, Lenny and Garrido, Carmen and Kolb, Martin and Bonniaud, Philippe and Goirand, Francoise and Bellaye, Pierre-Simon}, doi = {10.3390/ijms22179316}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {32373006}, issn = {1661-6596}, abstract = {Interstitial lung diseases (ILDs) include a large number of diseases and causes with variable outcomes often associated with progressive fibrosis. Although each of the individual fibrosing ILDs are rare, collectively, they affect a considerable number of patients, representing a significant burden of disease. Idiopathic pulmonary fibrosis (IPF) is the typical chronic fibrosing ILD associated with progressive decline in lung. Other fibrosing ILDs are often associated with connective tissues diseases, including rheumatoid arthritis-ILD (RA-ILD) and systemic sclerosis-associated ILD (SSc-ILD), or environmental/drug exposure. Given the vast number of progressive fibrosing ILDs and the disparities in clinical patterns and disease features, the course of these diseases is heterogeneous and cannot accurately be predicted for an individual patient. As a consequence, the discovery of novel biomarkers for these types of diseases is a major clinical challenge. Heat shock proteins (HSPs) are molecular chaperons that have been extensively described to be involved in fibrogenesis. Their extracellular forms (eHSPs) have been recently and successfully used as therapeutic targets or circulating biomarkers in cancer. The current review will describe the role of eHSPs in fibrosing ILDs, highlighting the importance of these particular stress proteins to develop new therapeutic strategies and discover potential biomarkers in these diseases.}, keywords = {biomarker; lung fibrosis; Heat shock proteins; Interstitial lung diseases; IPF; extracellular HSP}, year = {2021}, eissn = {1422-0067} } @article{MTMT:32373008, title = {Biomarkers of Radiotherapy-Induced Immunogenic Cell Death}, url = {https://m2.mtmt.hu/api/publication/32373008}, author = {Vaes, Rianne D. W. and Hendriks, Lizza E. L. and Vooijs, Marc and De Ruysscher, Dirk}, doi = {10.3390/cells10040930}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {10}, unique-id = {32373008}, abstract = {Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.}, keywords = {INTERFERON; Biomarkers; RADIOTHERAPY; Hsp70; HMGB1; calreticulin; Necroptosis; Immunogenic cell death}, year = {2021}, eissn = {2073-4409}, orcid-numbers = {Vooijs, Marc/0000-0003-1386-3027} } @article{MTMT:32373010, title = {First Virtual International Congress on Cellular and Organismal Stress Responses, November 5-6, 2020}, url = {https://m2.mtmt.hu/api/publication/32373010}, author = {van Oosten-Hawle, Patricija and Bergink, Steven and Blagg, Brian and Brodsky, Jeff and Edkins, Adrienne and Freeman, Brian and Genest, Olivier and Hendershot, Linda and Kampinga, Harm and Johnson, Jill and De Maio, Antonio and Masison, Dan and Morano, Kevin and Multhoff, Gabriele and Prodromou, Chris and Prahlad, Veena and Scherz-Shouval, Ruth and Zhuravleva, Anastasia and Mollapour, Mehdi and Truman, Andrew W.}, doi = {10.1007/s12192-021-01192-7}, journal-iso = {CELL STRESS CHAPERON}, journal = {CELL STRESS & CHAPERONES}, volume = {26}, unique-id = {32373010}, issn = {1355-8145}, abstract = {Members of the Cell Stress Society International (CSSI), Patricija van Oosten-Hawle (University of Leeds, UK), Mehdi Mollapour (SUNY Upstate Medical University, USA), Andrew Truman (University of North Carolina at Charlotte, USA) organized a new virtual meeting format which took place on November 5-6, 2020. The goal of this congress was to provide an international platform for scientists to exchange data and ideas among the Cell Stress and Chaperones community during the Covid-19 pandemic. Here we will highlight the summary of the meeting and acknowledge those who were honored by the CSSI.}, keywords = {Hsp70; HSP90; Heat shock proteins; chaperones; STRESS RESPONSES; Proteostasis; cancer biology; CSSI Congress}, year = {2021}, eissn = {1466-1268}, pages = {289-295}, orcid-numbers = {Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:32288543, title = {Hsp70 in Liquid Biopsies-A Tumor-Specific Biomarker for Detection and Response Monitoring in Cancer}, url = {https://m2.mtmt.hu/api/publication/32288543}, author = {Werner, Caroline and Stangl, Stefan and Salvermoser, Lukas and Schwab, Melissa and Shevtsov, Maxim and Xanthopoulos, Alexia and Wang, Fei and Dezfouli, Ali Bashiri and Tholke, Dennis and Ostheimer, Christian and Medenwald, Daniel and Windberg, Martin and Bache, Matthias and Schlapschy, Martin and Skerra, Arne and Multhoff, Gabriele}, doi = {10.3390/cancers13153706}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {13}, unique-id = {32288543}, abstract = {Simple Summary Tumor-specific biomarkers in liquid biopsies provide useful tools for detection of tumors, monitoring of tumor responses and prediction of outcomes. Nearly all malignant solid tumor cells, but not normal cells, present the major stress-inducible Heat shock protein 70 (Hsp70) on their cell surface and actively release it into the blood in small extracellular vesicles. Therefore, vesicular Hsp70 might serve as a biomarker for viable tumor cells. Presently, no validated test system is available that allows the quantification of vesicular Hsp70 in the blood. Based on two Hsp70-specific monoclonal antibodies, we have developed the complete (comp)Hsp70 ELISA that provides a highly sensitive and reliable tool for measuring both, free and vesicular Hsp70 in the circulation of tumor patients. Hsp70 levels in the blood reflect the presence and risk characteristics of tumors and their membrane-Hsp70 status, and might be predictive for therapeutic responses. In contrast to normal cells, tumor cells of multiple entities overexpress the Heat shock protein 70 (Hsp70) not only in the cytosol, but also present it on their plasma membrane in a tumor-specific manner. Furthermore, membrane Hsp70-positive tumor cells actively release Hsp70 in small extracellular vesicles with biophysical characteristics of exosomes. Due to conformational changes of Hsp70 in a lipid environment, most commercially available antibodies fail to detect membrane-bound and vesicular Hsp70. To fill this gap and to assess the role of vesicular Hsp70 in circulation as a potential tumor biomarker, we established the novel complete (comp)Hsp70 sandwich ELISA, using two monoclonal antibodies (mAbs), that is able to recognize both free and lipid-associated Hsp70 on the cell surface of viable tumor cells and on small extracellular vesicles. The epitopes of the mAbs cmHsp70.1 (aa 451-461) and cmHsp70.2 (aa 614-623) that are conserved among different species reside in the substrate-binding domain of Hsp70 with measured affinities of 0.42 nM and 0.44 nM, respectively. Validation of the compHsp70 ELISA revealed a high intra- and inter-assay precision, linearity in a concentration range of 1.56 to 25 ng/mL, high recovery rates of spiked liposomal Hsp70 (>84%), comparable values between human serum and plasma samples and no interference by food intake or age of the donors. Hsp70 concentrations in the circulation of patients with glioblastoma, squamous cell or adeno non-small cell lung carcinoma (NSCLC) at diagnosis were significantly higher than those of healthy donors. Hsp70 concentrations dropped concomitantly with a decrease in viable tumor mass upon irradiation of patients with approximately 20 Gy (range 18-22.5 Gy) and after completion of radiotherapy (60-70 Gy). In summary, the compHsp70 ELISA presented herein provides a sensitive and reliable tool for measuring free and vesicular Hsp70 in liquid biopsies of tumor patients, levels of which can be used as a tumor-specific biomarker, for risk assessment (i.e., differentiation of grade III vs. IV adeno NSCLC) and monitoring of therapeutic outcomes.}, keywords = {PREDICTION; Hsp70; glioblastoma; sandwich ELISA; Small extracellular vesicles; liquid biopsy; tumor biomarker; Non-small cell lung carcinoma (NSCLC); response monitoring}, year = {2021}, eissn = {2072-6694}, orcid-numbers = {Shevtsov, Maxim/0000-0002-8539-2239; Medenwald, Daniel/0000-0001-8920-2853; Skerra, Arne/0000-0002-5717-498X; Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:31424041, title = {HSP70 Multi-Functionality in Cancer}, url = {https://m2.mtmt.hu/api/publication/31424041}, author = {Albakova, Zarema and Armeev, Grigoriy A. and Kanevskiy, Leonid M. and Kovalenko, Elena I and Sapozhnikov, Alexander M.}, doi = {10.3390/cells9030587}, journal-iso = {CELLS-BASEL}, journal = {CELLS}, volume = {9}, unique-id = {31424041}, abstract = {The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer "addiction" to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.}, keywords = {APOPTOSIS; CANCER; METASTASIS; immunotherapy; Hsp70; senescence; Exosomes; Authophagy}, year = {2020}, eissn = {2073-4409}, orcid-numbers = {Albakova, Zarema/0000-0002-6281-8532; Kovalenko, Elena I/0000-0001-8119-8247} } @article{MTMT:31481659, title = {Monitoring HSP70 exosomes in cancer patients' follow up: a clinical prospective pilot study}, url = {https://m2.mtmt.hu/api/publication/31481659}, author = {Chanteloup, Gaetan and Cordonnier, Marine and Isambert, Nicolas and Bertaut, Aurelie and Hervieu, Alice and Hennequin, Audrey and Luu, Maxime and Zanetta, Sylvie and Coudert, Bruno and Bengrine, Leila and Desmoulins, Isabelle and Favier, Laure and Lagrange, Aurelie and Pages, Pierre-Benoit and Gutierrez, Ivan and Lherminier, Jeanine and Avoscan, Laure and Jankowski, Clementine and Rebe, Cedric and Chevriaux, Angelique and Padeano, Marie-Martine and Coutant, Charles and Ladoire, Sylvain and Causeret, Sylvain and Arnould, Laurent and Charon-Barra, Celine and Cottet, Vanessa and Blanc, Julie and Binquet, Christine and Bardou, Marc and Garrido, Carmen and Gobbo, Jessica}, doi = {10.1080/20013078.2020.1766192}, journal-iso = {J EXTRACELLULAR VESICL}, journal = {JOURNAL OF EXTRACELLULAR VESICLES}, volume = {9}, unique-id = {31481659}, abstract = {Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.}, keywords = {CANCER; diagnosis; Hsp70; Exosomes; liquid biopsy}, year = {2020}, eissn = {2001-3078} } @article{MTMT:31691440, title = {Association of Plasma Heat Shock Protein 70 with Disease Severity, Smoking and Lung Function of Patients with Chronic Obstructive Pulmonary Disease}, url = {https://m2.mtmt.hu/api/publication/31691440}, author = {Hlapcic, Iva and Hulina-Tomaskovic, Andrea and Rajkovic, Marija Grdic and Popovic-Grle, Sanja and Dugac, Andrea Vukic and Rumora, Lada}, doi = {10.3390/jcm9103097}, journal-iso = {J CLIN MED}, journal = {JOURNAL OF CLINICAL MEDICINE}, volume = {9}, unique-id = {31691440}, abstract = {Extracellular heat shock protein 70 (eHsp70) might modulate immune responses in chronic obstructive pulmonary disease (COPD). The aim of the study was to explore eHsp70 concentration in stable COPD, its association with disease severity and smoking status as well as its diagnostic performance in COPD assessment. Plasma samples were collected from 137 COPD patients and 95 healthy individuals, and concentration of eHsp70 was assessed by commercially available enzyme-linked immunosorbent assay (ELISA) kit (Enzo Life Science, Farmingdale, NY, USA). COPD patients were subdivided regarding airflow obstruction severity and symptoms severity according to the Global Initiative for COPD (GOLD) guidelines. eHsp70 concentration increased in COPD patients when compared to controls and increased with the severity of airflow limitation as well as symptoms burden and exacerbation history. eHsp70 concentration did not differ among COPD patients based on smoking status, yet it increased in healthy smokers compared to healthy nonsmokers. In addition, eHsp70 negatively correlated with lung function parameters forced expiratory volume in one second (FEV1) and FEV1/ forced vital capacity (FVC), and positively with COPD multicomponent indices BODCAT (BMI, airflow obstruction, dyspnea, CAT score), BODEx (BMI, airflow obstruction, dyspnea, previous exacerbations), CODEx (Charlson's comorbidity index, airflow obstruction, dyspnea, previous exacerbations) and DOSE (dyspnea, airflow obstruction, smoking status, previous exacerbations) With great predictive value (OR = 7.63) obtained from univariate logistic regression, eHsp70 correctly classified 76% of cases. eHsp70 is associated with COPD prediction and disease severity and might have the potential for becoming an additional biomarker in COPD assessment.}, keywords = {smoking; lung function; chronic obstructive pulmonary disease; EDTA plasma; extracellular heat shock protein 70}, year = {2020}, eissn = {2077-0383} } @article{MTMT:31489890, title = {The blood cells in NSCLC and the changes after RFA}, url = {https://m2.mtmt.hu/api/publication/31489890}, author = {Li, Yunfang and Wang, Dongdong and Li, Xiaoguang}, doi = {10.1080/02656736.2020.1782486}, journal-iso = {INT J HYPERTHER}, journal = {INTERNATIONAL JOURNAL OF HYPERTHERMIA}, volume = {37}, unique-id = {31489890}, issn = {0265-6736}, abstract = {Lung cancer has attracted a lot of attention because of its high morbidity and mortality. The emergence of RFA provides a new treatment for unresectable NSCLC patients. In addition to killingin situlung tumors, RFA also provides new immuno-activated antigens, for the treatment of lung cancer. It changes the tumor microenvironment and activates the entire immune system of patients. The peripheral blood cell count is easy to achieve and the blood cells are important in tumor immunity, which changes after RFA. On the one hand, the changes in blood cells identify the immune changes of NSCLC; on the other hand, it provides support and suspicion for the treatment of RFA.}, keywords = {blood cell; Immune; NSCLC; Tumor microenvironment; RFA}, year = {2020}, eissn = {1464-5157}, pages = {753-762} } @article{MTMT:31295876, title = {Heat shock proteins as biomarkers of lung cancer}, url = {https://m2.mtmt.hu/api/publication/31295876}, author = {Mittal, S. and Rajala, M.S.}, doi = {10.1080/15384047.2020.1736482}, journal-iso = {CANCER BIOL THER}, journal = {CANCER BIOLOGY & THERAPY}, volume = {21}, unique-id = {31295876}, issn = {1538-4047}, abstract = {Heat shock proteins are known to be associated with a wide variety of human cancers including lung cancer. Overexpression of these molecular chaperones is linked with tumor survival, metastasis and anticancer drug resistance. In recent years, heat shock proteins are gaining much importance in the field of cancer research owing to their potential to be key determinants of cell survival and apoptosis. Lung cancer is one of the most common cancers diagnosed worldwide and the association of heat shock proteins in lung cancer diagnosis, prognosis and as drug targets remains unresolved. The aim of this review is to draw the importance of heat shock protein members; Hsp27, Hsp70, Hsp90, Hsp60 and their diagnostic and prognostic implications in lung cancer. Based on the available literature heat shock proteins can serve as biomarkers and anticancer drug targets in the management of lung cancer patients. © 2020, © 2020 Taylor & Francis Group, LLC.}, keywords = {Prognosis; diagnosis; immunotherapy; biomarker; EGFR; NSCLC; HSP}, year = {2020}, eissn = {1555-8576}, pages = {477-485} } @{MTMT:31489888, title = {Hypoxia Compromises Anti-Cancer Immune Responses}, url = {https://m2.mtmt.hu/api/publication/31489888}, author = {Multhoff, Gabriele and Vaupel, Peter}, booktitle = {OXYGEN TRANSPORT TO TISSUE XLI}, doi = {10.1007/978-3-030-34461-0_18}, unique-id = {31489888}, abstract = {Hypoxia, one of the hallmarks of cancer, is caused by an insufficient oxygen supply, mostly due to a chaotic, deficient tumor microcirculation. Apart from a hypoxia-mediated resistance to standard therapies, modulated gene and protein expression, genetic instability and malignant progression, hypoxia also plays a pivotal role in anti-cancer immune responses by (a) reducing survival, cytolytic and migratory activity of effector cells such as CD4+ cells, CD8+ cytotoxic T cells, natural killer-like T cells and natural killer cells, (b) reducing the production and release of effector cytokines, (c) supporting immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells and M2 macrophages, (d) increasing the production and release of immunosuppressive cytokines, and (e) inducing the expression of immune checkpoint inhibitors. In this minireview, immunosuppressive effects of hypoxia- and HIF-1a-driven traits in cancers are described.}, keywords = {immunosuppression; HYPOXIA; tumor hypoxia; Anti-cancer immunity; Tumor microenvironment HIF-1 alpha hypoxia; Immunosuppressive cells hypoxia; Immunosuppressive factors}, year = {2020}, pages = {131-143} } @article{MTMT:31687044, title = {Targeted Natural Killer Cell-Based Adoptive Immunotherapy for the Treatment of Patients with NSCLC after Radiochemotherapy: A Randomized Phase II Clinical Trial}, url = {https://m2.mtmt.hu/api/publication/31687044}, author = {Multhoff, Gabriele and Seier, Sophie and Stangl, Stefan and Sievert, Wolfgang and Shevtsov, Maxim and Werner, Caroline and Pockley, A. Graham and Blankenstein, Christiane and Hildebrandt, Martin and Offner, Robert and Ahrens, Norbert and Kokowski, Konrad and Hautmann, Matthias and Roedel, Claus and Fietkau, Rainer and Lubgan, Dorota and Huber, Rudolf and Hautmann, Hubert and Duell, Thomas and Molls, Michael and Specht, Hanno and Haller, Bernhard and Devecka, Michal and Sauter, Andreas and Combs, Stephanie E.}, doi = {10.1158/1078-0432.CCR-20-1141}, journal-iso = {CLIN CANCER RES}, journal = {CLINICAL CANCER RESEARCH}, volume = {26}, unique-id = {31687044}, issn = {1078-0432}, abstract = {Purpose: Non-small cell lung cancer (NSCLC) is a fatal disease with poor prognosis. Amembrane-bound form of Hsp70 (mHsp70) which is selectively expressed on high-risk tumors serves as a target for mHsp70-targeting natural killer (NK) cells. Patients with advanced mHsp70-positive NSCLC may therefore benefit from a therapeutic intervention involving mHsp70-targeting NK cells. The randomized phase II clinical trial (EudraCT2008-002130-30) explores tolerability and efficacy of ex vivo-activated NK cells in patients with NSCLC after radiochemotherapy (RCT).Patients and Methods: Patients with unresectable, mHsp70-positive NSCLC (stage IIIa/b) received 4 cycles of autologous NK cells activated ex vivo with TKD/IL2 [interventional arm (INT)] after RCT (60-70 Gy, platinum-based chemotherapy) or RCT alone [control arm (CTRL)]. The primary objective was progression-free survival (PFS), and secondary objectives were the assessment of quality of life (QoL, QLQ-LC13), toxicity, and immunobiological responses.Results: The NK-cell therapy after RCT was well tolerated, and no differences in QoL parameters between the two study arms were detected. Estimated 1-year probabilities for PFS were 67% [95% confidence interval (CI), 19%-90%] for the INT arm and 33% (95% CI, 5%-68%) for the CTRL arm (P = 0.36, 1-sided logrank test). Clinical responses in the INT group were associated with an increase in the prevalence of activated NK cells in their peripheral blood.Conclusions: Ex vivo TKD/IL2-activated, autologous NK cells are well tolerated and deliver positive clinical responses in patients with advanced NSCLC after RCT.}, year = {2020}, eissn = {1557-3265}, pages = {5368-5379}, orcid-numbers = {Shevtsov, Maxim/0000-0002-8539-2239} } @article{MTMT:30981268, title = {Editorial: Combinatorial Approaches to Enhance Anti-tumor Immunity: Focus on Immune Checkpoint Blockade Therapy}, url = {https://m2.mtmt.hu/api/publication/30981268}, author = {Andersson, Patrik and Ostheimer, Christian}, doi = {10.3389/fimmu.2019.02083}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {10}, unique-id = {30981268}, issn = {1664-3224}, keywords = {CANCER; immunotherapy; RADIOTHERAPY; antiangiogenic therapy; cancer vaccine; immune checkpoint blockade (ICB)}, year = {2019}, eissn = {1664-3224} } @article{MTMT:30422120, title = {Hsp70 interactions with membrane lipids regulate cellular functions in health and disease.}, url = {https://m2.mtmt.hu/api/publication/30422120}, author = {Balogi, Zsolt and Multhoff, Gabrielle and Jensen, Thomas Kirkegaard and Lloyd-Evans, Emyr and Yamashima, Tetsumori and Jäättelä, Marja and Harwood, John L and Vigh, László}, doi = {10.1016/j.plipres.2019.01.004}, journal-iso = {PROG LIPID RES}, journal = {PROGRESS IN LIPID RESEARCH}, volume = {74}, unique-id = {30422120}, issn = {0163-7827}, abstract = {Beyond guarding the cellular proteome the major stress inducible heat shock protein Hsp70 has been shown to interact with lipids. Non-cytosolic Hsp70 stabilizes membranes during stress challenges and, in pathophysiological states, facilitates endocytosis, counteracts apoptotic mechanisms, sustains survival pathways or represents a signal that can be recognized by the immune system. Disease-coupled lipid-associated functions of Hsp70 may be targeted via distinct subcellular localizations of Hsp70 itself or its specific interacting lipids. With a special focus on interacting lipids, here we discuss localization-dependent roles of the membrane-bound Hsp70 in the context of its therapeutic potential, particularly in cancer and neurodegenerative diseases.}, year = {2019}, eissn = {1873-2194}, pages = {18-30} } @article{MTMT:30981271, title = {Netrin-1 interference potentiates epithelial-to-mesenchymal transition through the PI3K/AKT pathway under the hypoxic microenvironment conditions of non-small cell lung cancer}, url = {https://m2.mtmt.hu/api/publication/30981271}, author = {Jin, Xiayun and Luan, Heqi and Chai, Hua and Yan, Lina and Zhang, Jing and Wang, Qi and Cao, Lihua}, doi = {10.3892/ijo.2019.4716}, journal-iso = {INT J ONCOL}, journal = {INTERNATIONAL JOURNAL OF ONCOLOGY}, volume = {54}, unique-id = {30981271}, issn = {1019-6439}, abstract = {Netrin-1 is overexpressed in several types of cancer. However, whether netrin-1 can potentiate hypoxia-induced tumor progression in lung cancer has not been reported to date. Thus, the objective of the present study was to investigate whether netrin-1 regulates cancer cell migration and invasion under hypoxic conditions in lung cancer and explore the underlying mechanism. A three-dimensional microfluidic chip was used to observe real-time changes in cancer cells, and cobalt chloride (CoCl2) was used to simulate a hypoxic microenvironment. Netrin-1 siRNA was employed in the A549 and PC9 cell lines to downregulate the expression of netrin-1. Microfluidic chip, wound healing and Transwell assays were used to examine cell migration and invasion. The expression levels of E-cadherin and vimentin were detected by western blotting. The data demonstrated that netrin-1 mediated epithelial-to-mesenchymal transition (EMT) of A549 and PC9 cells in vitro, which may be associated with the phosphoinositide 3 kinase/AKT pathway. This effect of netrin-1 on the EMT was not observed in the normoxic microenvironment. In this retrospective study, netrin-1 concentrations were evaluated in serum obtained from patients with non-small cell lung cancer (NSCLC) and compared with healthy control samples by quantitative enzyme-linked immunosorbent analysis. The serum concentration of netrin-1 was found to be significantly higher in NSCLC patients compared with that in healthy donors. Taken together, the findings of the present study highlight a novel role for netrin-1 in tumor development under hypoxia in NSCLC and provide further evidence for the use of netrin-1 as a therapeutic target.}, keywords = {Epithelial-to-mesenchymal transition; Netrin-1; non-smal cell lung cancer}, year = {2019}, eissn = {1791-2423}, pages = {1457-1465} } @article{MTMT:30673182, title = {Radiochemotherapy combined with NK cell transfer followed by second-line PD-1 inhibition in apatient with NSCLC stage IIIb inducing long-term tumor control: acase study}, url = {https://m2.mtmt.hu/api/publication/30673182}, author = {Kokowski, Konrad and Stangl, Stefan and Seier, Sophie and Hildebrandt, Martin and Vaupel, Peter and Multhoff, Gabriele}, doi = {10.1007/s00066-019-01434-9}, journal-iso = {STRAHLENTHER ONKOL}, journal = {STRAHLENTHERAPIE UND ONKOLOGIE}, volume = {195}, unique-id = {30673182}, issn = {0179-7158}, year = {2019}, eissn = {1439-099X}, pages = {352-361} } @article{MTMT:30981267, title = {Cytosolic Hsp70 as a biomarker to predict clinical outcome in patients with glioblastoma}, url = {https://m2.mtmt.hu/api/publication/30981267}, author = {Laemmer, Friederike and Delbridge, Claire and Wuerstle, Silvia and Neff, Frauke and Meyer, Bernhard and Schlegel, Juergen and Kessel, Kerstin A. and Schmid, Thomas E. and Schilling, Daniela and Combs, Stephanie E.}, doi = {10.1371/journal.pone.0221502}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {14}, unique-id = {30981267}, issn = {1932-6203}, abstract = {IntroductionThe major stress-inducible heat shock protein 70 (Hsp70) is induced after different stress stimuli. In tumors, elevated intracellular Hsp70 levels were associated on the one hand with radio- and chemotherapy resistance and on the other hand with a favorable outcome for patients. This study was undertaken to investigate cytosolic Hsp70 (cHsp70) as a potential biomarker for progression free (PFS) and overall survival (OS) in patients with primary glioblastomas (GBM).MethodsThe cHsp70 expression in tumor tissue of 60 patients diagnosed with primary GBM was analyzed by immunohistochemistry. The cHsp70 expression was correlated to the PFS and OS of the patients.ResultsA high cHsp70 expression was associated with a prolonged PFS (hazard ratio = 0.374, p = 0.001) and OS (hazard ratio = 0.416, p = 0.014) in GBM patients treated according to the standard Stupp protocol with surgery, radiotherapy and temozolomide.ConclusionsThese data suggest that the intracellular Hsp70 expression might serve as a prognostic marker in patients with primary GBM.}, year = {2019}, eissn = {1932-6203} } @article{MTMT:30981270, title = {Increased heat shock protein 70 (Hsp70) serum levels and low NK cell counts after radiotherapy - potential markers for predicting breast cancer recurrence?}, url = {https://m2.mtmt.hu/api/publication/30981270}, author = {Rothammer, Anna and Sage, Eva K. and Werner, Caroline and Combs, Stephanie E. and Multhoff, Gabriele}, doi = {10.1186/s13014-019-1286-0}, journal-iso = {RADIAT ONCOL}, journal = {RADIATION ONCOLOGY}, volume = {14}, unique-id = {30981270}, issn = {1748-717X}, abstract = {BackgroundBreast cancer is the most common invasive tumor in women worldwide and the second cause of cancer-related deaths. After breast conserving surgery the tumor bed gets irradiated. Radiation-induced tumor cell death has been found to be associated with the release of damage-associated molecular patterns (DAMPs) including free Hsp70 that can stimulate inflammatory immune responses. Therefore, Hsp70 serum levels as well as the composition of lymphocyte subpopulations have been measured in breast cancer patients during therapy and in the follow-up period as potential predictors for clinical outcome.MethodsThe serum of 40 breast cancer patients, who received a breast-conserving surgery and adjuvant radiotherapy (RT) was examined for soluble, free Hsp70 using the R&D Human HSP70 DuoSet and lipHsp70 ELISA. Lymphocyte subpopulations and total lymphocyte counts were analysed by multiparameter flow cytometry in the peripheral blood. Blood samples were collected before (t1), after 30Gy (t2) and 60Gy (t3), 6weeks (t4), 6months (t5) and 1year (t6) after RT. Clinical responses were assessed regularly up to 5years after RT.ResultsPatients who developed a contralateral recurrence or metastases within the first 2years after RT had significantly higher serum Hsp70 values at the end of RT (t3; p=0.03) up to 6weeks after RT (t4; p=0.007) compared to patients who either remained disease-free or developed a secondary endometrial carcinoma. Clinicopathological parameters such as age, tumor size, grading and TNM-stage of the resected tumors, adjuvant chemotherapy and irradiation dose did not affect serum Hsp70 levels. Elevated free Hsp70 levels might be indicative for a chronic inflammatory response which could support tumor recurrence. Lymphocyte subpopulation analysis revealed lower NK cell counts after RT in recurrence/metastases patients as compared to disease-free patients. In contrast, no significant changes were observed in the proportion of T and B cells.ConclusionLongitudinal elevated serum levels of free Hsp70 up to 6weeks after RT and dropping NK cell counts might be predictive for an unfavourable prognosis in patients with breast cancer.}, keywords = {RADIOTHERAPY; immunophenotyping; DAMPs; Breast carcinoma prediction; Free Hsp70}, year = {2019}, eissn = {1748-717X} } @article{MTMT:30819499, title = {7Hsp70 serum levels in pet dogs—a potential diagnostic biomarker for spontaneous round cell tumors}, url = {https://m2.mtmt.hu/api/publication/30819499}, author = {Salvermoser, L. and Dressel, S. and Schleißheimer, S. and Stangl, S. and Diederichs, C. and Wergin, M. and Bley, C.R. and Haller, B. and Multhoff, G.}, doi = {10.1007/s12192-019-01024-9}, journal-iso = {CELL STRESS CHAPERON}, journal = {CELL STRESS & CHAPERONES}, volume = {24}, unique-id = {30819499}, issn = {1355-8145}, abstract = {The concentration of circulating heat shock protein 70 (Hsp70) was measured in liquid biopsies of canine tumor patients as a potential biomarker. Compared with rodent tumor models, spontaneously occurring tumors in pet dogs reflect the clinical situation of human patients better, as dogs cohabitate with their owners in the same environment, reach a much older age than rodents, can provide blood samples much more frequently, and receive up-to-date medical care and, similar to humans, their tumors show a high genetic heterogeneity. Due to the species-specific sequence homology of human and canine Hsp70, two human enzyme-linked immunosorbent assay (ELISA) systems (R&D and lipHsp70) were used to measure canine Hsp70 concentrations in serum and plasma. In general, higher Hsp70 concentrations were found in serum compared with plasma samples of dogs, and the lipHsp70 ELISA detected higher peak concentrations of Hsp70 in a broader range than the R&D ELISA. Compared with a tumor-free control group, serum Hsp70 concentrations were higher in tumor-bearing dogs, irrespective of breed, age, body weight, and gender. A sub-classification of the different tumors according to their cytological characteristics revealed significantly elevated Hsp70 serum concentrations in dogs with round cell tumors (p < 0.01), a heterogeneous group of malignancies with hematopoietic origin such as mast cells, plasma cells, lymphocytes, histiocytes, and melanomas. Future studies with larger patient cohorts and well-defined tumor sizes are necessary to elucidate the role of serum Hsp70 as a biomarker for tumor detection and monitoring of outcome in pet animals. © 2019, The Author(s).}, keywords = {tumor biomarker; mast cell tumor; round cell tumor; Canine Hsp70; lipHsp70 ELISA}, year = {2019}, eissn = {1466-1268}, pages = {969-978} } @article{MTMT:30673183, title = {Ex vivo Hsp70-Activated NK Cells in Combination With PD-1 Inhibition Significantly Increase Overall Survival in Preclinical Models of Glioblastoma and Lung Cancer}, url = {https://m2.mtmt.hu/api/publication/30673183}, author = {Shevtsov, Maxim and Pitkin, Emil and Ischenko, Alexander and Stangl, Stefan and Khachatryan, William and Galibin, Oleg and Edmond, Stanley and Lobinger, Dominik and Multhoff, Gabriele}, doi = {10.3389/fimmu.2019.00454}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {10}, unique-id = {30673183}, issn = {1664-3224}, year = {2019}, eissn = {1664-3224} } @article{MTMT:30860654, title = {Cancer takes a toll on skeletal muscle by releasing heat shock proteins—an emerging mechanism of cancer-induced cachexia}, url = {https://m2.mtmt.hu/api/publication/30860654}, author = {Sin, T.K. and Zhang, G. and Zhang, Z. and Gao, S. and Li, M. and Li, Y.-P.}, doi = {10.3390/cancers11091272}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {11}, unique-id = {30860654}, keywords = {CANCER; TLR4; Hsp70; HSP90; Muscle wasting}, year = {2019}, eissn = {2072-6694} } @article{MTMT:30907702, title = {Roles of Extracellular HSPs as Biomarkers in Immune Surveillance and Immune Evasion}, url = {https://m2.mtmt.hu/api/publication/30907702}, author = {Taha, Eman A. and Ono, Kisho and Eguchi, Takanori}, doi = {10.3390/ijms20184588}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {20}, unique-id = {30907702}, issn = {1661-6596}, abstract = {Extracellular heat shock proteins (ex-HSPs) have been found in exosomes, oncosomes, membrane surfaces, as well as free HSP in cancer and various pathological conditions, also known as alarmins. Such ex-HSPs include HSP90 (alpha, beta, Gp96, Trap1), HSP70, and large and small HSPs. Production of HSPs is coordinately induced by heat shock factor 1 (HSF1) and hypoxia-inducible factor 1 (HIF-1), while matrix metalloproteinase 3 (MMP-3) and heterochromatin protein 1 are novel inducers of HSPs. Oncosomes released by tumor cells are a major aspect of the resistance-associated secretory phenotype (RASP) by which immune evasion can be established. The concepts of RASP are: (i) releases of ex-HSP and HSP-rich oncosomes are essential in RASP, by which molecular co-transfer of HSPs with oncogenic factors to recipient cells can promote cancer progression and resistance against stresses such as hypoxia, radiation, drugs, and immune systems; (ii) RASP of tumor cells can eject anticancer drugs, targeted therapeutics, and immune checkpoint inhibitors with oncosomes; (iii) cytotoxic lipids can be also released from tumor cells as RASP. ex-HSP and membrane-surface HSP (mHSP) play immunostimulatory roles recognized by CD91+ scavenger receptor expressed by endothelial cells-1 (SREC-1)+ Toll-like receptors (TLRs)+ antigen-presenting cells, leading to antigen cross-presentation and T cell cross-priming, as well as by CD94+ natural killer cells, leading to tumor cytolysis. On the other hand, ex-HSP/CD91 signaling in cancer cells promotes cancer progression. HSPs in body fluids are potential biomarkers detectable by liquid biopsies in cancers and tissue-damaged diseases. HSP-based vaccines, inhibitors, and RNAi therapeutics are also reviewed.}, keywords = {immunology; biomarker; HYPOXIA; exosome; alarmin; Immune Surveillance; heat shock protein (HSP); immune evasion; oncosome; resistance-associated secretory phenotype (RASP)}, year = {2019}, eissn = {1422-0067}, orcid-numbers = {Eguchi, Takanori/0000-0002-3297-6126} } @article{MTMT:30981269, title = {Serum proteomics identify potential biomarkers for nasopharyngeal carcinoma sensitivity to radiotherapy}, url = {https://m2.mtmt.hu/api/publication/30981269}, author = {Zhang, Guangying and Zhang, Kun and Li, Chao and Li, Yanyan and Li, Zhanzhan and Li, Na and Zhou, Qin and Shen, Liangfang}, doi = {10.1042/BSR20190027}, journal-iso = {BIOSCIENCE REP}, journal = {BIOSCIENCE REPORTS}, volume = {39}, unique-id = {30981269}, issn = {0144-8463}, abstract = {Radiotherapy is the primary treatment option for nasopharyngeal carcinoma (NPC). Local recurrence and metastasis caused by radioresistance become a bottleneck of curative effect for patients with NPC. Currently, serum predictive biomarkers of radioresistance are scare. We enrolled NPC patients, who underwent radiotherapy in the Department of Oncology, Xiangya Hospital, Central Southern University, and analyzed the serum proteins profiles in NPC patients using with quantitative label-free proteomics using ultra-definition MS. Patients were divided into those who were radioresistant and radiosensitive by the overall reduction (<= 50% or >50%, respectively) in tumor extent. The MS/MS spectrum database search identified 911 proteins and 809 proteins are quantitatable. Eight proteins significantly up-regulated and 12 serum proteins were significantly down-regulated in the radioresistance group compared with radiosensitivity group (P<0.05). Finally, five proteins entered the optimal models, including secreted protein acidic and cysteine rich (SPARC) (P=0.032), serpin family D member 1S (ERPIND1) (P=0.040), complement C4B (C4B) (P=0.017), peptidylprolyl Isomerase B (PPIB) (P=0.042), and family with sequence similarity 173 member A (FAM173A) (P=0.017). In all patient, the area under the curves (AUC) for SPARC, SERPIND, C4B, PPIB, and FAM173A were 0.716 (95% CI: 0.574-0.881), 0.697 (95% CI: 0.837-0.858), 0.686 (95% CI: 0.522-0.850), 0.668 (95% CI: 0.502-0.834) and 0.657 (95% CI: 0.512-0.825), respectively. The AUC of five selected proteins was 0.968 (95% CI: 0.918-1.000) with the sensitivity of 0.941 and the specificity of 0.926. Our result indicated that a panel including five serum protein (SPARC SERPIND1 C4B PPIB FAM173A) based on serum proteomics provided a high discrimination ability for radiotherapy effects in NPC patients. Studies with larger sample size and longer follow-up outcome are required.}, year = {2019}, eissn = {1573-4935} } @article{MTMT:30364525, title = {High serum Hsp70 level predicts poor survival in colorectal cancer: Results obtained in an independent validation cohort}, url = {https://m2.mtmt.hu/api/publication/30364525}, author = {Gráf, László and Barabás, Loránd and Madaras, B. and Garam, Nóra and Maláti, É. and Horváth, Laura and Prohászka, Zoltán and Horváth, Zsolt and Kocsis, Judit}, doi = {10.3233/CBM-181683}, journal-iso = {CANCER BIOMARK}, journal = {CANCER BIOMARKERS}, volume = {23}, unique-id = {30364525}, issn = {1574-0153}, year = {2018}, eissn = {1875-8592}, pages = {539-547}, orcid-numbers = {Barabás, Loránd/0000-0001-7246-2739; Garam, Nóra/0000-0002-1959-4473; Horváth, Laura/0000-0001-8457-3647; Prohászka, Zoltán/0000-0003-1761-7982; Horváth, Zsolt/0000-0002-5376-7737; Kocsis, Judit/0000-0002-6110-9750} } @article{MTMT:30981272, title = {HSP70i(Q435A)-Encoding DNA Repigments Vitiligo Lesions in Sinclair Swine}, url = {https://m2.mtmt.hu/api/publication/30981272}, author = {Henning, Steven W. and Fernandez, Manuel F. and Mahon, James P. and Duff, Richard and Azarafrooz, Farshid and Guevara-Patino, Jose A. and Rademaker, Alfred W. and Salzman, Andrew L. and Le Poole, I. Caroline}, doi = {10.1016/j.jid.2018.06.186}, journal-iso = {J INVEST DERMATOL}, journal = {JOURNAL OF INVESTIGATIVE DERMATOLOGY}, volume = {138}, unique-id = {30981272}, issn = {0022-202X}, abstract = {Human HSP70i(Q435A) carries a single amino-acid modification within the dendritic cell activating region and tolerizes dendritic cells in vitro. The underlying DNA was used to prevent and treat disease in vitiligo mouse models through reduced dendritic cell activation and diminished skin T-cell infiltration, suggesting the same may be useful for patients. Physiologic differences between mouse and human skin then called for studies in large animals with human-like skin. We established the efficiency of DNA jet injection into swine skin before subcloning HSP70i(Q435A) into clinically suitable vector pUMVC3. Vitiligo lesions in Sinclair swine were treated with plasmid DNA to measure changes in depigmentation, T-cell infiltration, expression of HSP70i in skin, serum HSP70i, and anti-HSP70i serum titers. Remarkable repigmentation following HSP70i(Q435A)-encoding DNA treatment persisted throughout the 6-month follow-up period. Repigmentation was accompanied by an initial influx of T cells accompanied by increased CD4/CD8 ratios, waning by week 15. Melanocytes spanned the border of repigmenting skin, suggesting that melanocyte repopulation precedes skin melanization. Serum titer fluctuations were not treatment-associated. Importantly, treatment did not interfere with melanoma immunosurveillance. These data encourage clinical testing of HSP70i(Q435A).}, year = {2018}, eissn = {1523-1747}, pages = {2531-2539} } @article{MTMT:30981273, title = {Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume}, url = {https://m2.mtmt.hu/api/publication/30981273}, author = {Ostheimer, C. and Evers, C. and Bache, M. and Reese, T. and Vordermark, D.}, doi = {10.1007/s00066-017-1255-1}, journal-iso = {STRAHLENTHER ONKOL}, journal = {STRAHLENTHERAPIE UND ONKOLOGIE}, volume = {194}, unique-id = {30981273}, issn = {0179-7158}, abstract = {Background The urokinase plasminogen activator system (uPA, uPAR, PAIaEuro1) is upregulated in cancer and high plasma levels are associated with poor prognosis. Their interaction with hypoxia-related osteopontin (OPN) which is also overexpressed in malignant tumors suggests potential clinical relevance. However, the prognostic role of the uPA system in the radiotherapy (RT) of non-small-cell lung cancer (NSCLC), particularly in combination with OPN, has not been investigated so far.Methods uPA, uPAR, PAIaEuro1 and OPN plasma levels of 81 patients with locally advanced or metastasized NSCLC were prospectively analyzed by ELISA before RT and were correlated to clinical patient/tumor data and prognosis after RT.Results uPAR plasma levels were higher in M1; uPA and PAIaEuro1 levels were higher in M0 NSCLC patients. uPAR correlated with uPA (p < 0.001) which also correlated with PAIaEuro1 (p < 0.001). The prognostic impact of OPN plasma levels in the RT of NSCLC was previously reported by our group. PAIaEuroI plasma levels significantly impacted overall (OS) and progression-free survival (PFS). Low PAIaEuro1 levels were associated with a significantly reduced OS and PFS with a nearly 2aEurofold increased risk of death (p=0.029) and tumor progression (p=0.029). In multivariate analysis, PAIaEuro1 levels remained an independent prognostic factor for OS and PFS with a 3aEurofold increased risk of death (p=0.001). If PAIaEuro1 plasma levels were combined with OPN or tumor volume, we found an additive prognostic impact on OS and PFS with a 2.5- to 3aEurofold increased risk of death (p=0.01).Our results suggest that PAI-1 but not uPA and uPAR might add prognostic information in patients with advanced NSCLC undergoing RT. High pretreatment PAI-1 plasma levels were found predominantly in M0-stage patients and indicate a favorable prognosis as opposed to OPN where high plasma levels are associated with poor survival and metastasis. In combination, PAI-1 and OPN levels successfully predicted outcome and additively correlated with prognosis. These findings support the notion of an antidromic prognostic impact of OPN and PAI-1 plasma levels in the RT of advanced NSCLC.}, keywords = {Prognosis; RADIOTHERAPY; biomarker; non-small-cell lung cancer (NSCLC); Urokinase plasminogen activator (uPA); Plasminogen-activator inhibitor 1 (PAI-1); Urokinase plasminogen activator receptor ( uPAR)}, year = {2018}, eissn = {1439-099X}, pages = {539-551} } @article{MTMT:30369461, title = {Clinical, prognostic and therapeutic significance of heat shock proteins in cancer}, url = {https://m2.mtmt.hu/api/publication/30369461}, author = {Saini, J. and Sharma, P.K.}, doi = {10.2174/1389450118666170823121248}, journal-iso = {CURR DRUG TARGETS}, journal = {CURRENT DRUG TARGETS}, volume = {19}, unique-id = {30369461}, issn = {1389-4501}, year = {2018}, eissn = {1873-5592}, pages = {1478-1490} } @article{MTMT:30510976, title = {Membrane heat shock protein 70: a theranostic target for cancer therapy}, url = {https://m2.mtmt.hu/api/publication/30510976}, author = {Shevtsov, Maxim and Huile, Gao and Multhoff, Gabriele}, doi = {10.1098/rstb.2016.0526}, journal-iso = {PHILOS T ROY SOC B}, journal = {PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B - BIOLOGICAL SCIENCES}, volume = {372}, unique-id = {30510976}, issn = {0962-8436}, abstract = {Members of the 70 kDa stress protein family are found in nearly all subcellular compartments of nucleated cells where they fulfil a number of chaperoning functions. Heat shock protein 70 (HSP70), also termed HSPA1A, the major stress-inducible member of this family is overexpressed in a large variety of different tumour types. Apart from its intracellular localization, a tumour-selective HSP70 membrane expression has been determined. A membrane HSP70-positive tumour phenotype is associated with aggressiveness and therapy resistance, but also serves as a recognition structure for targeted therapies. Furthermore, membrane-bound and extracellularly residing HSP70 derived from tumour cells play pivotal roles in eliciting anti-tumour immune responses. Herein, we want to shed light on the multiplicity of different activities of HSP70, depending on its intracellular, membrane and extracellular localization with the goal to use membrane HSP70 as a target for novel therapies including nanoparticle-based approaches for the treatment of cancer.}, keywords = {CANCER; theranostic; nanoparticle therapy; HSP70 targeting}, year = {2018}, eissn = {1471-2970}, orcid-numbers = {Multhoff, Gabriele/0000-0002-2616-3137} } @article{MTMT:27602786, title = {Heat shock protein 70 and tumor-infiltrating NK cells as prognostic indicators for patients with squamous cell carcinoma of the head and neck after radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG)}, url = {https://m2.mtmt.hu/api/publication/27602786}, author = {Stangl, Stefan and Tontcheva, Nikoletta and Sievert, Wolfgang and Shevtsov, Maxim and Niu, Minli and Schmid, Thomas E and Pigorsch, Steffi and Combs, Stephanie E and Haller, Bernhard and Balermpas, Panagiotis and Roedel, Franz and Roedel, Claus and Fokas, Emmanouil and Krause, Mechthild and Linge, Annett and Lohaus, Fabian and Baumann, Michael and Tinhofer, Inge and Budach, Volker and Stuschke, Martin and Grosu, Anca-Ligia and Abdollahi, Amir and Debus, Juergen and Belka, Claus and Maihoefer, Cornelius and Moennich, David and Zips, Daniel and Multhoff, Gabriele}, doi = {10.1002/ijc.31213}, journal-iso = {INT J CANCER}, journal = {INTERNATIONAL JOURNAL OF CANCER}, volume = {142}, unique-id = {27602786}, issn = {0020-7136}, year = {2018}, eissn = {1097-0215}, pages = {1911-1925} } @article{MTMT:30981274, title = {Circulating Heat Shock Protein 70 Is a Novel Biomarker for Early Diagnosis of Lung Cancer}, url = {https://m2.mtmt.hu/api/publication/30981274}, author = {Tang, Tielong and Yang, Chao and Brown, Ham Ebo and Huang, Jing}, doi = {10.1155/2018/6184162}, journal-iso = {DIS MARKERS}, journal = {DISEASE MARKERS}, unique-id = {30981274}, issn = {0278-0240}, abstract = {Heat shock protein 70 (HSP70) was a highly conserved protein which was significantly induced in response to cellular stresses. HSP70 played an important role in the pathogenesis of cancer which stabilized the production of large amount of oncogenic proteins and finally supported growth and survival of tumor. However, there was no report about the diagnosis of circulating HSP70 in lung cancer patients. In this study, a total of 297 participants (lung cancer: 197, healthy control: 100) were enrolled in the detection of circulating HSP70 level in plasma by ELISA assay. The results indicated that circulating HSP70 significantly decreased in lung cancer patients compared to healthy controls (P < 0 0001). Receiver operating characteristic (ROC) analysis showed that HSP70 (AUC: 82.2%, SN: 74.1%, SP: 80.0%) had higher diagnosis value than clinical existing biomarkers CEA (AUC: 80.1%, SN: 76.8%, SP: 67.3%) and CA 19-9 (AUC: 63.7%, SN: 64.2%, SP: 54.0%). In the analysis of early lung cancer patients, ROC results also revealed that HSP70 (AUC: 83.8%, SN: 71.2%, SP: 84.0%) have higher sensitivity, specificity, and AUC than CEA (AUC: 73.7%, SN: 73.2%, SP: 69.1%) and CA 19-9 (AUC: 61.5%, SN: 69.4%, SP: 53.4%). In analysis of specific histological classifications, HSP70 showed more valuable in the diagnosis of SCC (AUC: 85.9%, SN: 86.1.9%, SP: 81.0%) than ADC (AUC: 81.0%, SN: 69.1%, SP: 81.0%). Combined analysis of HSP70 and existing biomarker: CEA and CA 19-9 exhibited that HSP70 combined CEA and CA 19-9 showed the highest AUC (0.945, 95% CI, 0.855-1.000). The importance of our results was that we found decreased circulating HSP70, in combination with elevated CEA and CA 19-9, could be utilized in the diagnosis of early (stage I and II) lung cancer.}, year = {2018}, eissn = {1875-8630} } @article{MTMT:30981275, title = {Immunomodulation by ionizing radiation-impact for design of radio-immunotherapies and for treatment of inflammatory diseases}, url = {https://m2.mtmt.hu/api/publication/30981275}, author = {Frey, Benjamin and Rueckert, Michael and Deloch, Lisa and Ruehle, Paul F. and Derer, Anja and Fietkau, Rainer and Gaipl, Udo S.}, doi = {10.1111/imr.12572}, journal-iso = {IMMUNOL REV}, journal = {IMMUNOLOGICAL REVIEWS}, volume = {280}, unique-id = {30981275}, issn = {0105-2896}, abstract = {Ionizing radiation is often regarded as an element of danger. But, danger responses on the cellular and molecular level are often beneficial with regard to the induction of anti-tumor immunity and for amelioration of inflammation. We outline how in dependence of radiation dose and fraction, radiation itself-and especially in combination with immune modulators-impacts on the innate and adaptive immune system. Focus is set on radiation-induced changes of the tumor cell phenotype and the cellular microenvironment including immunogenic cancer cell death. Mechanisms how anti-tumor immune responses are triggered by radiotherapy in combination with hyperthermia, inhibition of apoptosis, the adjuvant AnnexinA5, or vaccination with high hydrostatic pressure-killed autologous tumor cells are discussed. Building on this, feasible multimodal radio-immunotherapy concepts are reviewed including overcoming immune suppression by immune checkpoint inhibitors and by targeting TGF-. Since radiation-induced tissue damage, inflammation, and anti-tumor immune responses are interconnected, the impact of lower doses of radiation on amelioration of inflammation is outlined. Closely meshed immune monitoring concepts based on the liquid biopsy blood are suggested for prognosis and prediction of cancer and non-cancer inflammatory diseases. Finally, challenges and visions for the design of cancer radio-immunotherapies and for treatment of benign inflammatory diseases are given.}, keywords = {Inflammation; ionizing radiation; in situ vaccination; Immunomonitoring; immunogenic cancer cell death; radio-immunotherapy}, year = {2017}, eissn = {1600-065X}, pages = {231-248}, orcid-numbers = {Frey, Benjamin/0000-0001-6743-3351; Deloch, Lisa/0000-0002-5577-2302} } @article{MTMT:30981276, title = {Systemic effects of ionizing radiation at the proteome and metabolome levels in the blood of cancer patients treated with radiotherapy: the influence of inflammation and radiation toxicity}, url = {https://m2.mtmt.hu/api/publication/30981276}, author = {Jelonek, Karol and Pietrowska, Monika and Widlak, Piotr}, doi = {10.1080/09553002.2017.1304590}, journal-iso = {INT J RADIAT BIOL}, journal = {INTERNATIONAL JOURNAL OF RADIATION BIOLOGY}, volume = {93}, unique-id = {30981276}, issn = {0955-3002}, abstract = {Purpose: Blood is the most common replacement tissue used to study systemic responses of organisms to different types of pathological conditions and environmental insults. Local irradiation during cancer radiotherapy induces whole body responses that can be observed at the blood proteome and metabolome levels. Hence, comparative blood proteomics and metabolomics are emerging approaches used in the discovery of radiation biomarkers. These techniques enable the simultaneous measurement of hundreds of molecules and the identification of sets of components that can discriminate different physiological states of the human body. Radiation-induced changes are affected by the dose and volume of irradiated tissues; hence, the molecular composition of blood is a hypothetical source of biomarkers for dose assessment and the prediction and monitoring of systemic responses to radiation. This review aims to provide a comprehensive overview on the available evidence regarding molecular responses to ionizing radiation detected at the level of the human blood proteome and metabolome. It focuses on patients exposed to radiation during cancer radiotherapy and emphasizes effects related to radiation-induced toxicity and inflammation.Conclusions: Systemic responses to radiation detected at the blood proteome and metabolome levels are primarily related to the intensity of radiation-induced toxicity, including inflammatory responses. Thus, several inflammation-associated molecules can be used to monitor or even predict radiation-induced toxicity. However, these abundant molecular features have a rather limited applicability as universal biomarkers for dose assessment, reflecting the individual predisposition of the immune system and tissue-specific mechanisms involved in radiation-induced damage.}, keywords = {PLASMA; SERUM; proteomics; metabolomics; ionizing radiation; LIPIDOMICS; normal tissue toxicity}, year = {2017}, eissn = {1362-3095}, pages = {683-696}, orcid-numbers = {Jelonek, Karol/0000-0002-7233-7695; Pietrowska, Monika/0000-0001-9317-7822; Widlak, Piotr/0000-0001-5099-4726} } @article{MTMT:3276578, title = {Circulating mitochondrial stress 70 protein/mortalin and cytosolic Hsp70 in blood: Risk indicators in colorectal cancer.}, url = {https://m2.mtmt.hu/api/publication/3276578}, author = {Jubran, R and Kocsis, Judit and Garam, Nóra and Malati, E and Gombos, Tímea and Barabás, Loránd and Gráf, László and Prohászka, Zoltán and Fishelson, Z}, doi = {10.1002/ijc.30918}, journal-iso = {INT J CANCER}, journal = {INTERNATIONAL JOURNAL OF CANCER}, volume = {141}, unique-id = {3276578}, issn = {0020-7136}, abstract = {Mitochondrial mortalin and cytosolic Hsp70 are essential chaperones overexpressed in cancer cells. Our goals were to reproduce our earlier findings of elevated circulating levels of mortalin and Hsp70 in colorectal cancer (CRC) patients with a larger patient cohort, to compare death risk assessment of mortalin, Hsp70, CEA and C19-9 and to assess their prognostic value in various CRC stages. Mortalin, Hsp70, CEA and CA19-9 levels were determined in sera of 235 CRC patients enrolled in the study and followed up 5 years after surgery. Association between their concentrations and patients' survival was analyzed by Kaplan-Meier estimator and subjected to Cox Proportional hazards analysis. Serum level of mortalin was independent of that of Hsp70, CEA and CA19-9, whereas Hsp70 level weakly correlated with CEA and CA19-9 levels. Improved short-term survival was found in early or advanced disease stages associated with lower mortalin and Hsp70 levels. Cox regression analysis showed a high mortality hazard (HR = 3.7, p < 0.001) in patients with both high mortalin and Hsp70 circulating levels. Multivariate analysis showed that high mortalin and Hsp70 significantly enhances risk score over a baseline model of age, number of affected lymph nodes, CEA, CA19-9, disease stage and perioperative therapy. Analysis of mortalin and Hsp70 in CRC patients' sera adds a high prognostic value to TNM stage and to CEA and CA19-9 and identifies patients with lower or higher survival probability in all CRC stages. Determination of mortalin and Hsp70 in blood could be a useful additive prognostic tool in guiding clinical management of patients.}, year = {2017}, eissn = {1097-0215}, pages = {2329-2335}, orcid-numbers = {Kocsis, Judit/0000-0002-6110-9750; Garam, Nóra/0000-0002-1959-4473; Gombos, Tímea/0000-0002-0413-3586; Barabás, Loránd/0000-0001-7246-2739; Prohászka, Zoltán/0000-0003-1761-7982} } @article{MTMT:30981277, title = {Role of Natural Killer Cells in HIV-Associated Malignancies}, url = {https://m2.mtmt.hu/api/publication/30981277}, author = {Leal, Fabio E. and Premeaux, Thomas A. and Abdel-Mohsen, Mohamed and Ndhlovu, Lishomwa C.}, doi = {10.3389/fimmu.2017.00315}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {8}, unique-id = {30981277}, issn = {1664-3224}, abstract = {Now in its fourth decade, the burden of HIV disease still persists, despite significant milestone achievements in HIV prevention, diagnosis, treatment, care, and support. Even with long-term use of currently available antiretroviral therapies (ARTs), eradication of HIV remains elusive and now poses a unique set of challenges for the HIV-infected individual. The occurrence of HIV-associated non-AIDS-related comorbidities outside the scope of AIDS-defining illnesses, in particular non-AIDS-defining cancers, is much greater than the age-matched uninfected population. The underlying mechanism is now recognized in part to be related to the immune dysregulated and inflammatory status characteristic of HIV infection that persists despite ART. Natural killer (NK) cells are multifunctional effector immune cells that play a critical role in shaping the innate immune responses to viral infections and cancer. NK cells can modulate the adaptive immune response via their role in dendritic cell (DC) maturation, removal of immature tolerogenic DCs, and their ability to produce immunoregulatory cytokines. NK cells are therefore poised as attractive therapeutic targets that can be harnessed to control or clear both HIV and HIV-associated malignancies. To date, features of the tumor microenvironment and the evolution of NK-cell function among individuals with HIV-related malignancies remain unclear and may be distinct from malignancies observed in uninfected persons. This review intends to uncouple anti-HIV and antitumor NK-cell features that can be manipulated to halt the evolution of HIV disease and HIV-associated malignancies and serve as potential preventative and curative immunotherapeutic options.}, keywords = {CANCER; HIV; natural killer cells; LYMPHOMA; ADCC; Antiretroviral therapy; eradication and control}, year = {2017}, eissn = {1664-3224} } @article{MTMT:27048281, title = {Dynamics of Heat Shock Protein 70 Serum Levels As a Predictor of Clinical Response in Non-Small-Cell Lung Cancer and Correlation with the Hypoxia-Related Marker Osteopontin}, url = {https://m2.mtmt.hu/api/publication/27048281}, author = {Ostheimer, Christian and Gunther, Sophie and Bache, Matthias and Vordermark, Dirk and Multhoff, Gabriele}, doi = {10.3389/fimmu.2017.01305}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {8}, unique-id = {27048281}, issn = {1664-3224}, year = {2017}, eissn = {1664-3224} } @article{MTMT:27285329, title = {Increased HSP27 correlates with malignant biological behavior of non-small cell lung cancer and predicts patient's survival}, url = {https://m2.mtmt.hu/api/publication/27285329}, author = {Sheng, Baowei and Qi, Congcong and Liu, Bing and Lin, Yong and Fu, Tian and Zeng, Qingdi}, doi = {10.1038/s41598-017-13956-2}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {7}, unique-id = {27285329}, issn = {2045-2322}, year = {2017}, eissn = {2045-2322} } @article{MTMT:27048280, title = {Overexpression of cytosolic, plasma membrane bound and extracellular heat shock protein 70 (Hsp70) in primary glioblastomas}, url = {https://m2.mtmt.hu/api/publication/27048280}, author = {Thorsteinsdottir, Jun and Stangl, Stefan and Fu, Peng and Guo, Ketai and Albrecht, Valerie and Eigenbrod, Sabina and Erl, Janina and Gehrmann, Mathias and Tonn, Jorg-Christian and Multhoff, Gabriele and Schichor, Christian}, doi = {10.1007/s11060-017-2600-z}, journal-iso = {J NEURO-ONCOL}, journal = {JOURNAL OF NEURO-ONCOLOGY}, volume = {135}, unique-id = {27048280}, issn = {0167-594X}, year = {2017}, eissn = {1573-7373}, pages = {443-452} } @article{MTMT:26535685, title = {Genotoxic stress modulates the release of exosomes from multiple myeloma cells capable of activating NK cell cytokine production: Role of HSP70/TLR2/NF-kB axis}, url = {https://m2.mtmt.hu/api/publication/26535685}, author = {Vulpis, Elisabetta and Cecere, Francesca and Molfetta, Rosa and Soriani, Alessandra and Fionda, Cinzia and Peruzzi, Giovanna and Caracciolo, Giulio and Palchetti, Sara and Masuelli, Laura and Simonelli, Lucilla and D'Oro, Ugo and Abruzzese, Maria Pia and Petrucci, Maria Teresa and Ricciardi, Maria Rosaria and Paolini, Rossella and Cippitelli, Marco and Santoni, Angela and Zingoni, Alessandra}, doi = {10.1080/2162402X.2017.1279372}, journal-iso = {ONCOIMMUNOLOGY}, journal = {ONCOIMMUNOLOGY}, volume = {6}, unique-id = {26535685}, issn = {2162-4011}, year = {2017}, eissn = {2162-402X}, orcid-numbers = {Molfetta, Rosa/0000-0003-2904-6371} } @article{MTMT:26893293, title = {Tumor induces muscle wasting in mice through releasing extracellular Hsp70 and Hsp90}, url = {https://m2.mtmt.hu/api/publication/26893293}, author = {Zhang, Guohua and Liu, Zhelong and Ding, Hui and Zhou, Yong and Hoang, Anh Doan and Sin, Ka Wai Thomas and Zhu, Zhiren J and Flores, Rene and Wen, Yefei and Gong, Xing and Liu, Qingyun and Li, Yi-Ping}, doi = {10.1038/s41467-017-00726-x}, journal-iso = {NAT COMMUN}, journal = {NATURE COMMUNICATIONS}, volume = {8}, unique-id = {26893293}, issn = {2041-1723}, year = {2017}, eissn = {2041-1723} } @article{MTMT:25797989, title = {Targeting Hsp70: A possible therapy for cancer}, url = {https://m2.mtmt.hu/api/publication/25797989}, author = {Kumar, Sanjay and Stokes, James III and Singh, Udai P and Gunn, Karyn Scissum and Acharya, Arbind and Manne, Upender and Mishra, Manoj}, doi = {10.1016/j.canlet.2016.01.056}, journal-iso = {CANCER LETT}, journal = {CANCER LETTERS}, volume = {374}, unique-id = {25797989}, issn = {0304-3835}, year = {2016}, eissn = {1872-7980}, pages = {156-166} } @article{MTMT:25798367, title = {The human HSP70 family of chaperones: where do we stand?}, url = {https://m2.mtmt.hu/api/publication/25798367}, author = {Radons, Jurgen}, doi = {10.1007/s12192-016-0676-6}, journal-iso = {CELL STRESS CHAPERON}, journal = {CELL STRESS & CHAPERONES}, volume = {21}, unique-id = {25798367}, issn = {1355-8145}, year = {2016}, eissn = {1466-1268}, pages = {379-404} } @article{MTMT:30981278, title = {Immunological and Translational Aspects of NK Cell-Based Antitumor Immunotherapies}, url = {https://m2.mtmt.hu/api/publication/30981278}, author = {Shevtsov, Maxim and Multhoff, Gabriele}, doi = {10.3389/fimmu.2016.00492}, journal-iso = {FRONT IMMUNOL}, journal = {FRONTIERS IN IMMUNOLOGY}, volume = {7}, unique-id = {30981278}, issn = {1664-3224}, abstract = {Natural killer (NK) cells play a pivotal role in the first line of defense against cancer. NK cells that are deficient in CD3 and a clonal T cell receptor (TCR) can be subdivided into two major subtypes, CD56(dim)CD16(+) cytotoxic and CD56(bright)CD16(-) immunoregulatory NK cells. Cytotoxic NK cells not only directly kill tumor cells without previous stimulation by cytotoxic effector molecules, such as perforin and granzymes or via death receptor interactions, but also act as regulatory cells for the immune system by secreting cytokines and chemokines. The aim of this review is to highlight therapeutic strategies utilizing autologous and allogenic NK cells, combinations of NK cells with monoclonal antibodies to induce antibody-dependent cellular cytotoxicity, or immune checkpoint inhibitors. Additionally, we discuss the use of chimeric antigen receptor-engineered NK cells in cancer immunotherapy.}, keywords = {immunotherapy; monoclonal antibody; natural killer cell; chimeric antigen receptor; antibody-dependent cellular cytotoxicity; checkpoint inhibitors}, year = {2016}, eissn = {1664-3224}, orcid-numbers = {Shevtsov, Maxim/0000-0002-8539-2239; Multhoff, Gabriele/0000-0002-2616-3137} }