The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment.
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.
Rolny
Charlotte
C
Institute for Cancer Research and Treatment (IRCC), University of Turin, School of Medicine, 10060 Candiolo, Italy.
Capparuccia
Lorena
L
Casazza
Andrea
A
Mazzone
Massimiliano
M
Vallario
Antonella
A
Cignetti
Alessandro
A
Medico
Enzo
E
Carmeliet
Peter
P
Comoglio
Paolo M
PM
Tamagnone
Luca
L
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*
D016209:Interleukin-8; D008562:Membrane Glycoproteins; C409766:SEMA3B protein, human; D039961:Semaphorins