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

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.

[1]  F. Rossi,et al.  Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis , 2007, BMC Developmental Biology.

[2]  Bruce H. Hasegawa,et al.  The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans , 2007, Proceedings of the National Academy of Sciences.

[3]  J. Gutkind,et al.  MT1-MMP Controls Tumor-induced Angiogenesis through the Release of Semaphorin 4D* , 2007, Journal of Biological Chemistry.

[4]  M. Sporn,et al.  The tumour microenvironment as a target for chemoprevention , 2007, Nature Reviews Cancer.

[5]  D. Wagner,et al.  Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury , 2007, Proceedings of the National Academy of Sciences.

[6]  J. Pollard,et al.  Macrophages regulate the angiogenic switch in a mouse model of breast cancer. , 2006, Cancer research.

[7]  P. Musiani,et al.  Triggering CD40 on endothelial cells contributes to tumor growth , 2006, The Journal of experimental medicine.

[8]  R. Ganss.  Tumor stroma fosters neovascularization by recuitment of progenitor cells into the tumor bed , 2006, Journal of cellular and molecular medicine.

[9]  P. Allavena,et al.  Role of tumor-associated macrophages in tumor progression and invasion , 2006, Cancer and Metastasis Reviews.

[10]  A. Zalatnai.  Molecular aspects of stromal-parenchymal interactions in malignant neoplasms. , 2006, Current molecular medicine.

[11]  J. Gutkind,et al.  Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[12]  S. Akira,et al.  Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis , 2006, Nature Cell Biology.

[13]  C. Betsholtz,et al.  Pericytes and vascular stability. , 2006, Experimental cell research.

[14]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[15]  J. Settleman,et al.  p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling , 2005, Journal of Cell Science.

[16]  K. Guan,et al.  Semaphorin 4D/Plexin-B1 Induces Endothelial Cell Migration through the Activation of PYK2, Src, and the Phosphatidylinositol 3-Kinase-Akt Pathway , 2005, Molecular and Cellular Biology.

[17]  P. Carmeliet,et al.  Common mechanisms of nerve and blood vessel wiring , 2005, Nature.

[18]  P. Comoglio,et al.  Sema4D induces angiogenesis through Met recruitment by Plexin B1. , 2005, Blood.

[19]  E. Medico,et al.  The MET oncogene drives a genetic programme linking cancer to haemostasis , 2005, Nature.

[20]  M. Cronin,et al.  A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. , 2004, The New England journal of medicine.

[21]  A. Shakya,et al.  Induction of the MMP-14 Gene in Macrophages of the Atherosclerotic Plaque: Role of SAF-1 in the Induction Process , 2004, Circulation research.

[22]  T. Furuyama,et al.  Sema4D stimulates axonal outgrowth of embryonic DRG sensory neurones , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[23]  K. Guan,et al.  Class IV Semaphorins Promote Angiogenesis by Stimulating Rho-Initiated Pathways through Plexin-B , 2004, Cancer Research.

[24]  P. Comoglio,et al.  Plexin signaling hampers integrin‐based adhesion, leading to Rho‐kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  J. Christensen,et al.  A selective small molecule inhibitor of c-Met kinase inhibits c-Met-dependent phenotypes in vitro and exhibits cytoreductive antitumor activity in vivo. , 2003, Cancer research.

[26]  P. Carmeliet.  Angiogenesis in health and disease , 2003, Nature Medicine.

[27]  P. Comoglio,et al.  Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. , 2003, Cancer cell.

[28]  R. Jaenisch,et al.  HIF-1α Is Essential for Myeloid Cell-Mediated Inflammation , 2003, Cell.

[29]  P. Circosta,et al.  CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. , 2003, Blood.

[30]  A. Kolodkin,et al.  Semaphorin junction: making tracks toward neural connectivity , 2003, Current Opinion in Neurobiology.

[31]  Giorgio F. Gilestro,et al.  The Semaphorin 4D receptor controls invasive growth by coupling with Met , 2002, Nature Cell Biology.

[32]  G. Bismuth,et al.  Controlling the Immune System Through Semaphorins , 2002, Science's STKE.

[33]  L. Trusolino,et al.  Scatter-factor and semaphorin receptors: cell signalling for invasive growth , 2002, Nature Reviews Cancer.

[34]  C. Tse,et al.  Human Semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. , 2002, Cancer research.

[35]  H. Kikutani,et al.  The CD100-CD72 interaction: a novel mechanism of immune regulation. , 2001, Trends in immunology.

[36]  J. Pollard.  Tumour-stromal interactions: Transforming growth factor-beta isoforms and hepatocyte growth factor/scatter factor in mammary gland ductal morphogenesis , 2001, Breast Cancer Research.

[37]  A. Elhabazi,et al.  Biological Activity of Soluble CD100. I. The Extracellular Region of CD100 Is Released from the Surface of T Lymphocytes by Regulated Proteolysis1 , 2001, The Journal of Immunology.

[38]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[39]  L. Naldini,et al.  Hepatocyte Growth Factor Is a Regulator of Monocyte-Macrophage Function1 , 2001, Journal of Immunology.

[40]  M. Ikawa,et al.  The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. , 2000, Immunity.

[41]  M. Matsumoto,et al.  Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. , 2000, Immunity.

[42]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages , 2000 .

[43]  Barbara Bottazzi,et al.  Autocrine Production of IL-10 Mediates Defective IL-12 Production and NF-κB Activation in Tumor-Associated Macrophages1 , 2000, The Journal of Immunology.

[44]  M. Kuwano,et al.  Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: Possible involvement of TNFα and IL‐1α , 2000 .

[45]  M. Poo,et al.  Plexins Are a Large Family of Receptors for Transmembrane, Secreted, and GPI-Anchored Semaphorins in Vertebrates , 1999, Cell.

[46]  S. Soker,et al.  Neuropilin-1 Mediates Collapsin-1/Semaphorin III Inhibition of Endothelial Cell Motility , 1999, The Journal of cell biology.

[47]  C. Goodman,et al.  Plexin A Is a Neuronal Semaphorin Receptor that Controls Axon Guidance , 1998, Cell.

[48]  J. Klingelhöfer,et al.  Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. , 1998, Cancer research.

[49]  G. Freeman,et al.  Human CD100, a novel leukocyte semaphorin that promotes B-cell aggregation and differentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Jeffrey A. Golden,et al.  Semaphorin III is needed for normal patterning and growth of nerves, bones and heart , 1996, Nature.

[51]  C. Goodman,et al.  The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules , 1993, Cell.

[52]  S. Yamagishi,et al.  Pericyte biology and diseases. , 2005, International journal of tissue reactions.

[53]  A. Harris,et al.  Macrophage infiltration and angiogenesis in human malignancy. , 2004, Novartis Foundation symposium.

[54]  R. Jaenisch,et al.  HIF-1alpha is essential for myeloid cell-mediated inflammation. , 2003, Cell.

[55]  A. Harris,et al.  The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. , 2000, The American journal of pathology.

[56]  M. Kuwano,et al.  Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha. , 2000, International journal of cancer.