Abstract 1474: Semaphorin 3A potentiates metastatic disease by binding to endothelial Neuropilin-1 and disrupting vascular barrier function

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Abstract We previously showed that Semaphorin 3A (Sema3A), a known inhibitor of axonal sprouting, inhibits VEGF-induced angiogenesis yet induces vascular permeability. In patient samples, immunohistochemical analysis of Sema3A showed that its expression increased with disease progression and metastasis. Similarly, Sema3A expression was higher in cell lines with enhanced metastatic potential. We considered whether Sema3A expression in a variety of highly malignant tumor cells might contribute to their metastatic properties based on Sema3A's capacity to disrupt vascular barrier function. To evaluate this, we stably knocked down Sema3A expression in CT26 (colon) and B16-BL6 (skin) cells and examined their growth and invasive properties both in vitro and in vivo. Loss of Sema3A significantly decreased the incidence of pulmonary lung metastasis. Importantly, Sema3A knockdown did not impair tumor cell adhesion, migration, proliferation, or anchorage-independent growth in vitro; and it had no effect on primary tumor growth and angiogenesis in vivo, suggesting a role for Sema3A in tumor cell extravasation. Furthermore, tamoxifen-inducible conditional knockout of the Sema3A receptor Neuropilin-1 (Nrp1) within the adult endothelium inhibited lung colonization and metastasis but had no effect on primary tumor growth. Similarly, a function blocking antibody against Nrp1 known to inhibit Sema3A-mediated permeability prevented lung colonization. Because Nrp1 is also a co-receptor for VEGF, we reintroduced a mutant of Nrp1 that lacks Sema3A but not VEGF binding capability into our tamoxifen-inducible endothelial-specific Nrp1 knockout mouse. Expression of mutant Nrp1 inhibited experimental metastasis, but not primary tumor growth confirming a specific role for Sema3A-Nrp1 interaction in extravasation. Together these findings define a pathological role for tumor cell secreted Sema3A as a potentiator of tumor cell metastasis and vascular barrier disruption. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1474. doi:10.1158/1538-7445.AM2011-1474