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¹ Institute for Cancer Research and Treatment (IRCC), University of Turin, School of Medicine, 10060 Candiolo, Italy
² Department of Transgene Technology and Gene Therapy (Flanders Institute for Biotechnology) and Center for Transgene Technology and Gene Therapy, Katholieke Universiteit Leuven, 3000 Leuven, Belgium

CORRESPONDENCE Luca Tamagnone: luca.tamagnone{at}ircc.it

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.

L. Capparuccia and A. Casazza contributed equally to this work.

C. Rolny's present address is Dept. of Genetics and Pathology, Unit of Vascular Biology, Rudbeck Laboratory, Uppsala University, S-751 85 Uppsala, Sweden.

© 2008 Rolny et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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• Eickholt, B. J. (2008). Functional diversity and mechanisms of action of the semaphorins. Development 135: 2689-2694 [Abstract] [Full Text]  

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