title: The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment.
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.
authors.affiliation: Institute for Cancer Research and Treatment (IRCC), University of Turin, School of Medicine, 10060 Candiolo, Italy.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Rolny
authors.forename: Lorena
authors.initials: L
authors.lastname: Capparuccia
authors.forename: Andrea
authors.initials: A
authors.lastname: Casazza
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.forename: Antonella
authors.initials: A
authors.lastname: Vallario
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cignetti
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Luca
authors.initials: L
authors.lastname: Tamagnone
mesh_terms: D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D017124:Conserved Sequence; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000502:physiology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000517:prevention & control; D016133:Polymerase Chain Reaction; D039961:Semaphorins / Q000235:genetics* / Q000502:physiology*
chemical_list: D016209:Interleukin-8; D008562:Membrane Glycoproteins; C409766:SEMA3B protein, human; D039961:Semaphorins