The antitumoral effects of chemerin are independent from leukocyte recruitment and mediated by inhibition of neoangiogenesis

Abstract

Chemerin, a multifunctional protein acting through the receptor ChemR23/CMKLR1, is downregulated in various human tumors and was shown to display antitumoral properties in mouse models of cancer. In the present study, we report that bioactive chemerin expression by tumor cells delays the growth of B16 melanoma and Lewis lung carcinoma in vivo . A similar delay is observed when chemerin is not expressed by tumor cells but by keratinocytes of the host mice. The protective effect of chemerin is mediated by CMKLR1 and appears unrelated to the recruitment of leukocyte populations. Rather, tumors grown in the presence of chemerin display a much smaller number of blood vessels, hypoxic regions early in their development, and larger necrotic areas. These observations likely explain the slower growth of the tumors. The anti-angiogenic effects of chemerin were confirmed in a bead sprouting assay using human umbilical vein endothelial cells. These results suggest that CMKLR1 agonists might constitute therapeutic molecules inhibiting the neoangiogenesis process in solid tumors.

Chemerin regulates normal angiogenesis and hypoxia-driven neovascularization

“…In our hands, chemerin had no effects on neovessel sprouting in the aorta ring assay, nor on migration or proliferation of HUVECs in culture. It should be noted however that we reported recently a strong inhibitory effect of chemerin on the extent of the capillary network formed by HUVECs in the bead sprouting assay [21].…”

“…We used B16-F0 melanoma and Lewis lung carcinoma (LLC), two models reported to progress in an angiogenesis-dependent manner [38,39]. As reported previously [21], grafting B16-F0 or LLC cells in K5-Chem mice resulted in smaller tumors than in control mice (Fig. 8a-c).…”

“…Chemerin was also described to display anti-tumoral properties in a number of cancer models, as well as protumoral effects in some others [54]. In previous studies, we described the anti-tumoral properties of chemerin in several models of cancer [19,21]. These effects were attributed to an inhibition of tumoral neoangiogenesis, leading to hypoxia and necrosis.…”

“…Chemerin was shown to display anti-tumoral properties in several mouse models [18,20]. In a recent study, we reported that these properties could be attributed to an inhibitory effect on the vascularization of tumors, resulting in necrotic cell death [21]. We investigated further whether this anti-angiogenic effect in a tumoral context could be mediated by a destabilization of neovessels.…”

“…We and others have identified chemerin as an anti-tumoral factor in different mouse models [18][19][20]. We recently proposed that, in mouse cancer graft models, the anti-tumoral activity of chemerin does not involve the recruitment of leukocyte populations but is mediated by the inhibition of the vascularization of the tumors, an effect mediated through CMKLR1 [21].…”