Semaphorin7A promotes tumor growth and exerts a pro-angiogenic effect in macrophages of mammary tumor-bearing mice

Abstract

Semaphorins are a large family of molecules involved in axonal guidance during the development of the nervous system and have been recently shown to have both angiogenic and anti-angiogenic properties. Specifically, semaphorin 7A (SEMA7A) has been reported to have a chemotactic activity in neurogenesis and to be an immune modulator through α1β1integrins. SEMA7A has been shown to promote monocyte chemotaxis and induce them to produce proinflammatory mediators. In this study we explored the role of SEMA7A in a murine model of breast cancer. We show that SEMA7A is highly expressed by DA-3 murine mammary tumor cells in comparison to normal mammary cells (EpH4), and that peritoneal elicited macrophages from mammary tumor-bearing mice also express SEMA7A at higher levels compared to those derived from normal mice. We also show that murine macrophages treated with recombinant murine SEMA7A significantly increased their expression of proangiogenic molecule CXCL2/MIP-2. Gene silencing of SEMA7A in peritoneal elicited macrophages from DA-3 tumor-bearing mice resulted in decreased CXCL2/MIP-2 expression. Mice implanted with SEMA7A silenced tumor cells showed decreased angiogenesis in the tumors compared to the wild type tumors. Furthermore, peritoneal elicited macrophages from mice bearing SEMA7A-silenced tumors produce significantly (p < 0.01) lower levels of angiogenic proteins, such as CXCL2/MIP-2, CXCL1, and MMP-9, compared to those from control DA-3 mammary tumors. We postulate that SEMA7A in mammary carcinomas may skew monocytes into a pro-tumorigenic phenotype to support tumor growth. SEMA7A could prove to be valuable in establishing new research avenues toward unraveling important tumor-host immune interactions in breast cancer patients.

Semaphorin 7A promotes EGFR-TKI resistance in EGFR mutant lung adenocarcinoma cells

“…We and others have demonstrated that SEMA7A activates ERK signals via integrin β1 (ITGB1) in neurons and macrophages (15,19,20). Several studies using mice or human samples demonstrated that SEMA7A expression promotes mammary tumor progression, epithelial-to-mesenchymal transition (EMT), and angiogenesis (21)(22)(23)(24). Moreover, SEMA7A promotes cell growth in oral squamous carcinoma (25), activates tumor-associated macrophages in melanoma (26), and correlates with invasiveness of a glioblastoma cell line (27).…”

Semaphorin 7A as a potential immune regulator and promising therapeutic target in rheumatoid arthritis

“…On the other hand, Sema7A has been shown to function as a regulator of the T-cell immune response by its effects on T-cell proliferation [16]. Notably, Sema7A has been demonstrated to have a clear effect on the migration processes of osteoblasts and osteoclasts in bone remodeling and a distinct role in tumor angiogenesis [17, 18]. Neovascularization, immunologic abnormality, and bone erosion all have crucial roles in the progression of RA [19, 20], suggesting that Sema7A may aggravate RA.…”

The role of the semaphorins in cancer

“…260 In metastatic melanomas, sema7A was reported to contribute to the metastasis of melanoma cells to lungs 261 and to function as a pro-angiogenic factor. 262 Likewise, it was reported to contribute to the metastasis of breast cancer cells by promoting epithelial to mesenchymal transition. 263 Recently, sema7A was found to be upregulated in oral squamous cell carcinoma, to promote their proliferation of these tumor cells, and to enhance their invasiveness.…”