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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

77 Citazioni (Scopus)

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. © 2008 Rolny et al. The Rockefeller University Press.
Lingua originaleEnglish
pagine (da-a)1155-1171
Numero di pagine17
RivistaJOURNAL OF EXPERIMENTAL MEDICINE
Volume205
DOI
Stato di pubblicazionePubblicato - 2008

Keywords

  • INTERLEUKIN 8
  • SEMAPHORIN 3B

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