The Journal of Experimental Medicine
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Published online June 16, 2008
doi:10.1084/jem.20072602
The Journal of Experimental Medicine, Vol. 205, No. 7, 1673-1685
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Sierra et al.
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ARTICLE

 Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

Jose Rafael Sierra1, Simona Corso1, Luisa Caione1, Virna Cepero1, Paolo Conrotto1, Alessandro Cignetti1, Wanda Piacibello1, Atsushi Kumanogoh2, Hitoshi Kikutani2, Paolo Maria Comoglio1, Luca Tamagnone1, and Silvia Giordano1

1 Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
2 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

CORRESPONDENCE Silvia Giordano: silvia.giordano{at}unito.it

Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321–4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target.

Abbreviations used: b-FGF, basic fibroblast growth factor; EC, endothelial cell; HGF, hepatocyte growth factor; HUVEC, human umbilical vein endothelial cell; MSR1, macrophage scavenger receptor 1; Sema4D, semaphorin 4D; TAM, tumor-associated macrophage; VSV, vesicular stomatitis virus.

P. Conrotto's present address is Dept. of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich, Switzerland.


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