Inhibition of Tumor-Derived Semaphorin7A Decreases Tumor Progression in a Murine Model of Metastatic by modulating production angiogenic chemokines and immune infiltration

Abstract It is estimated that one in eight women will be diagnosed with breast cancer. Developing an understanding of the tumor microenvironment is critical for developing treatments for breast cancer patients. Poorly differentiated blood vessels can fashion an oxygen-deprived microenvironment that triggers the expression of transcription factor Hypoxia Inducible Factor alpha (HIF-1alpha) that in turn can up regulate genes mediating a pro-tumor effect. Our laboratory has discovered that mammary tumors express Semaphorin7a (SEMA7A), a HIF-1alpha inducible protein. Tumor-derived SEMA7A induces monocytes to secrete proangiogenic chemokines to enhance tumor growth. Decreasing tumor-derived SEMA7A limits tumor growth and the production of angiogenic CXCL-2/MIP-2 and VEGF-A by monocytes. Immune cells also express elevated levels of SEMA7A in tumors, however the role of stromal-derived SEMA7A in tumorigenesis is largely unknown. We hypothesized that SEMA7A may be a hypoxia-inducible factor and that inhibition may deter the effects of hypoxia on tumor and immune cells. Following hypoxic stimuli, WT monocytes increased production of CXCL2, VEGF-A and Chitinase-3-like protein1. However, SEMA7A null monocytes failed to respond to hypoxia, which may be attributed to an impaired MAPK signaling response. Monocytes from SEMA KO tumor bearing mice showed a decreased production of angiogenic molecules. More importantly, we found that SEMA7A KO 4T1 mammary tumor bearing mice showed decreased tumor growth and metastasis compared to WT. Collectively, we show a role for not only a tumor-derived, but also stromal-derived SEMA7A in hypoxia-mediated mammary tumor progression.