Abstract 3438: Expression of a novel tumor-derived axonal guidance molecule Sema7a in a breast cancer model

Abstract

Abstract The purpose of this study is to explore the expression of axonal guidance molecule Sema7a by breast cancer cells and the possible hijacking of macrophages by Sema7a to promote tumor growth. We have recently identified the novel expression and secretion of axonal guidance molecule Sema7a by two different mouse mammary tumor cells both in vitro and in vivo. No studies have yet elucidated the implications of Sema7a expression in cancer. The over-expression of Sema7a in murine breast cancer cell lines may parallel the expression of this axonal guidance molecule in human breast cancer. Furthermore, we have evidence that Sema7a is expressed at higher levels in the macrophages and activated T lymphocytes of tumor bearers compared to the normal mice. To determine the role of the tumor on Sema7a expression, Sema7a expression was assessed in macrophages and T cells from normal mice cultured with tumor-derived factors. Sema7a, originally discovered for its chemotactic activity, is a known immune modulator through α1β1integrins. Sema7a mediates chemotaxis of human peripheral blood monocytes and induces them to produce proinflammatory cytokines, including IL-1β, IL-6, TNF-α, and IL-8. Murine macrophages treated with Sema7a significantly increased their expression of CXCL2/MIP-2 an angiogenic chemokine that is a homologue of human IL-8. This proinflammatory chemokine is known to promote leukocyte-mediated angiogenesis and tumor growth. Monocytes recruited to the tumor adopt a macrophage phenotype that is of M2. M2 macrophages secrete angiogenic factors including VEGF, IL-8, and TNF-α, as well as TNF-α-dependent MMP-9 that degrades extracellular matrix to promote metastasis. It is not clear which tumor-derived factors drive the switch to M2 phenotype in the macrophages and their subsequent production of angiogenic chemokines and matrix metalloproteinases. A putative relationship between tumor-derived Sema7a and monocytes could prove valuable in establishing new research avenues towards unraveling important tumor-host immune interactions in breast cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3438.