Abstract 3398: Double-faced Sema3E-PlexinD1 signaling inhibits tumor growth but promotes metastatic spreading

Semaphorins comprise a wide family of secreted and membrane-bound signals, originally found in neural development, and then implicated in a range of functions: from angiogenesis, to the immune response, to cancer progression. We have previously shown that high-affinity semaphorin receptors are found in the families of the plexins and of the neuropilins. Moreover, additional molecules interact with semaphorin receptors in cell-context dependent manner, featuring a complex scenario of multiple potential signaling pathways. The role of semaphorin signaling in tumor progression is currently under close scrutiny; it is known that cancer cells release semaphorins regulating their own behavior as well as that of cells in the tumor microenvironment, such as endothelial cells and recruited leukocytes. In this work, we focused on the function of Semaphorin 3E (Sema3E) and its high affinity receptor PlexinD1, and on their potential role to regulate cancer progression. Here we found that Sema3E and PlexinD1 are highly expressed in human metastatic tumors. Moreover, we provided experimental evidences that Sema3E released by tumor cells is a double-faced signal, acting via two distinctive signaling pathways. In paracrine manner, Sema3E-PlexinD1 signaling can elicit endothelial cell repulsion, thereby reducing vessel density and tumor growth. Conversely, Sema3E autocrine signaling in tumor cells thrusts their invasiveness, trans-endothelial migration, and metastatic spreading, through the trans-activation of PlexinD1-associated oncogenic kinases. Notably, by silencing the endogenous expression of either Sema3E or PlexinD1 the metastatic potential of cancer cells is significantly reduced, identifying this pathway as a major driver of the metastatic spreading. In sum, Sema3E autocrine signaling in cancer cells is crucially implicated to induce a metastatic behavior, and it appears as a promising target for strategies aimed at blocking tumor metastasis. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 3398.