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.
Solid tumors can generate a plethora of neurogenesis-related molecules that enhance their growth and metastasis. Among them, we have identified axonal guidance molecule Semaphorin 7A (SEMA7A) in breast cancer. The goal of this study was to determine the therapeutic effect of suppressing SEMA7A levels in the 4T1 murine model of advanced breast carcinoma. We used anti-SEMA7A short hairpin RNA (shRNA) to gene silence SEMA7A in 4T1 mammary tumor cells. When implanted into the mammary fat pads of syngeneic mice, SEMA7A shRNA-expressing 4T1 tumors exhibited decreased growth rates, deferred metastasis and reduced mortality. In vitro, SEMA7A shRNA-expressing 4T1 cells had weakened proliferative, migratory and invasive abilities, and decreased levels of mesenchymal factors. Atomic force microscopy studies showed that SEMA7A shRNA-expressing 4T1 cells had an increase in cell stiffness that corresponded with their decreased malignant potential. Genetic ablation of host-derived SEMA7A further enhanced the antitumor effects of SEMA7A shRNA gene silencing in 4T1 cells. Our preclinical findings demonstrate a critical role for SEMA7A in mediating mammary tumor progression.
The study of breast cancer relies heavily upon the identification of tumor-associated proteins that are involved with tumor growth and development. Our lab has discovered that mammary tumor cells express high levels of a novel protein known as Semaphorin7A (SEMA7A). After analyzing breast tissue samples collected at Boca Raton Regional Hospital, we have found that normal human mammary epithelial cells express negligible mRNA levels of SEMA7A, while the malignant mammary tumor cells express elevated levels of SEMA7A. Additionally, our laboratory has established a murine model of mammary cell lines that parallels our human findings. Currently, we have correlated high levels of SEMA7A with increasing tumor malignancy and metastasis. However, it is still unknown what factors could induce the production of SEMA7A in mammary tumors. Recent studies have proven that the expression and induction of SEMA7A in normal endothelial cells is regulated under a hypoxic-response element in the promoter of its gene. Although hypoxia is an established tumorigenic factor, it is unknown if the increased hypoxic conditions in breast tumors could induce SEMA7A. In this study we have investigated if exposing mammary cells to hypoxia induces the expression of pro-tumorgenic SEMA7A. Our results show that SEMA7A is up-regulated in 4T07 and 4T1 mammary tumor cells after hypoxic exposure via TGF-β activation of the PI3/AKT pathway. Furthermore, we have found that shRNA silencing of the SEMA7A in 4T1 mammary cells attenuates the activation of pro-angiogenic and mesenchymal genes even after hypoxic stimuli. In vivo, these cells show a reduced proliferation and metastatic potential. We therefore postulate an exciting new role for SEMA7A as a TGF-β effector that promotes tumorigenesis during breast cancer progression. Citation Format: Ramon A. Garcia-Areas, Stephania Libreros, Samantha Amat, Camila Castro-Silva, Kathy Schilling, Vijaya Iragavarapu-Charyulu. Hypoxia induced TGF-β regulates Semaphorin7A to promote a pro-tumorigenic mesenchymal phenotype in mammary cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2007. doi:10.1158/1538-7445.AM2014-2007
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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