Semaphorins are a large family of molecules involved in the axonal guidance and development of the nervous system. In addition, they also play important roles in immunomodulation. Semaphorin 7A (SEMA7A) has been reported to be a modulator of monocytes and macrophages via α1β1integrins. SEMA7A promotes chemotaxis of monocytes and induces them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in breast cancer. We first show that SEMA7A is highly expressed by DA-3, EO771 and 4T1 mammary tumor cells in comparison to normal mammary cells (EpH4). Furthermore, peritoneal elicited macrophages from mammary tumor-bearing mice express higher levels of SEMA7A compared to those from normal mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of angiogenic chemokine CXCL2 via activation of the MAPK pathway. Peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly lower levels of CXCL2, CXCL1 and MMP-9, compared to macrophages from control tumor bearers. Gene silencing of Sema7A in macrophages from tumor-bearers decreased in their angiogenic potential. We postulate that SEMA7A in mammary carcinomas may skew monocytes into a pro-tumorigenic phenotype to support tumor growth.
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