The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment

Charlotte Rolny, Lorena Capparuccia, Andrea Casazza, Massimiliano Mazzone, Antonella Vallario, Alessandro Cignetti, Enzo Medico, Peter Carmeliet, Paolo M. Comoglio, Luca Tamagnone

Research output: Contribution to journalArticle

Abstract

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules originally identified for their repelling role in axonal guidance. Intriguingly, semaphorins have recently been implicated in cancer progression (Neufeld, G., T. Lange, A. Varshavsky, and O. Kessler. 2007. Adv. Exp. Med. Biol. 600:118-131). In particular, semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. We found that SEMA3B induced the production of interleukin (IL) 8 by tumor cells by activating the p38-mitogen-activated protein kinase pathway in a neuropilin 1-dependent manner. Silencing the expression of endogenous SEMA3B in tumor cells impaired IL-8 transcription. The release of IL-8, in turn, induced the recruitment of tumor-associated macrophages and metastatic dissemination to the lung, which could be rescued by blocking IL-8 with neutralizing antibodies. In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth.

Original languageEnglish
Pages (from-to)1155-1171
Number of pages17
JournalJournal of Experimental Medicine
Volume205
Issue number5
DOIs
Publication statusPublished - May 12 2008

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ASJC Scopus subject areas

  • Immunology

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