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

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  • Jose Rafael Sierra
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Simona Corso
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Luisa Caione
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Virna Cepero
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Paolo Conrotto
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Alessandro Cignetti
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Wanda Piacibello
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Atsushi Kumanogoh
    2Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
  • Hitoshi Kikutani
    2Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
  • Paolo Maria Comoglio
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Luca Tamagnone
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy
  • Silvia Giordano
    1Institute for Cancer Research and Treatment, University of Torino Medical School, 10060 Candiolo (Torino), Italy

Description

<jats:p>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.</jats:p>

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