Within the tumor microenvironment, tumor cells and endothelial cells regulate each
other. While tumor cells induce angiogenic responses in endothelial cells, endothelial
cells release angiocrine factors, which act on tumor cells and other stromal cells.
We report that tumor cell–derived adrenomedullin has a pro-angiogenic as well as a
direct tumor-promoting effect, and that endothelium-derived CC chemokine ligand 2
(CCL2) suppresses adrenomedullin-induced tumor cell proliferation. Loss of the endothelial
adrenomedullin receptor CALCRL or of the G-protein Gs reduced endothelial proliferation.
Surprisingly, tumor cell proliferation was also reduced after endothelial deletion
of CALCRL or Gs. We identified CCL2 as a critical angiocrine factor whose formation
is inhibited by adrenomedullin. Furthermore, CCL2 inhibited adrenomedullin formation
in tumor cells through its receptor CCR2. Consistently, loss of endothelial CCL2 or
tumor cell CCR2 normalized the reduced tumor growth seen in mice lacking endothelial
CALCRL or Gs. Our findings show tumor-promoting roles of adrenomedullin and identify
CCL2 as an angiocrine factor controlling adrenomedullin formation by tumor cells.
