Semaphorin7A Inhibition interrupts hypoxia induction of angiogenic factors in murine monocytes (TUM6P.963)

We discovered that mammary tumor cells express high levels of the protein Semaphorin7A (SEMA7A) and that tumor-derived SEMA7A induces monocytes to secrete pro-angiogenic chemokines to enhance tumor growth. Decreased SEMA7A limits tumor growth and production of angiogenic CXCL-2/MIP-2 and VEGF-A by monocytes. The mechanisms controlling SEMA7A expression during tumor progression are largely unknown. Recent reports describe a hypoxia responsive element in the promoter of SEMA7A. It is well established that hypoxia enhances tumor growth by promoting angiogenesis and alternatively activating monocytes. We hypothesize that SEMA7A may be a hypoxia-inducible factor and its inhibition may deter production of monocyte-derived angiogenic proteins. Monocytes from wild-type (WT) and SEMA7A null BALB/c mice were exposed to CoCl 2 -induced hypoxia. CoCl 2 induced expression of SEMA7A in both mammary cells and WT monocytes. Following hypoxic stimuli, WT monocytes increased production of CXCL2/MIP-2, VEGF-A and Chitinase-3-like protein1 (CHI3L1). However, SEMA7A null monocytes failed to respond to hypoxia, which may be attributed to an impaired MAPK signaling response. Thus, inhibiting SEMA7A may abrogate the detrimental effects of tumor induced hypoxia on monocytes. We are further delineating how the lack of host SEMA7A can impact mammary tumor growth in vivo. Understanding the role of SEMA7A may unravel important tumor-host immune interactions in breast cancer.