Abstract 3268: Targeting Semaphorin signaling to inhibit tumor growth and metastatic spreading

Abstract

Abstract The Semaphorins and their receptors, Neuropilins and Plexins, were originally implicated as guidance signals in the development of the central nervous system. However, a growing body of evidence indicates that semaphorins may regulate tumor progression, by promoting or inhibiting tumor angiogenesis, tumor cell survival and metastatic spreading, in fact mediating a crosstalk between tumor cells and multiple stromal cell types in the surrounding microenvironment. Here, we provide two examples of the multifaceted activity of semaphorins during tumor progression. We found that Semaphorin 3A (SEMA3A) inhibits primary tumor growth and its metastatic dissemination by employing three different experimental approaches in mouse tumor models: (i) over-expression of SEMA3A in tumor cells; (ii) systemic expression of SEMA3A following gene transfer in mice; (iii) tumor-targeted release of SEMA3A using gene-modified Tie2-expressing monocytes (TEMs) as delivery vehicles. In each of these experimental settings, SEMA3A efficiently inhibited tumor growth by disrupting vessel function and inducing tumor hypoxia and necrosis, without promoting metastatic dissemination. Moreover, we have recently shown that another secreted semaphorin known to regulate angiogenesis, Semaphorin 3E (SEMA3E), is abundantly expressed in metastatic human tumors, where it promotes cancer cell invasiveness and metastatic spreading. Notably, this biological activity of SEMA3E depends on a proteolytic conversion by furin-like convertases, generating the active fragment “p61”-SEMA3E. In cancer cells, p61-SEMA3E induces the association of the receptor PlexinD1 with the oncogenic tyrosine-kinase receptor ErbB2, leading to ErbB2 activation and enhanced tumor invasion and metastasis. Here we show that a mutated uncleavable variant of SEMA3E (Uncl-SEMA3E) binds the receptor PlexinD1 but it is unable to trigger ErbB2 signaling in cancer cells and lacks any pro-metastatic activity. On the other hand, Uncl-SEMA3E functions as a potent anti-angiogenic factor and displays striking tumor-suppressor properties in vivo. In summary, SEMA3A and Uncl-SEMA3E are potent inhibitors of tumor angiogenesis and tumor growth which concomitantly block the metastatic spreading of tumor cells. These data provide evidence that support interfering with semaphorin-mediated signals as a promising anti-cancer strategy. 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 3268. doi:10.1158/1538-7445.AM2011-3268