PDGF-C Mediates the Angiogenic and Tumorigenic Properties of Fibroblasts Associated With Tumors Refractory to anti-VEGF Treatment

Cancer Cell. 2009 Jan 6;15(1):21-34. doi: 10.1016/j.ccr.2008.12.004.

Abstract

Tumor- or cancer-associated fibroblasts (TAFs or CAFs) from different tumors exhibit distinct angiogenic and tumorigenic properties. Unlike normal skin fibroblasts or TAFs from TIB6 tumors that are sensitive to anti-VEGF treatment (TAF-TIB6), TAFs from resistant EL4 tumors (TAF-EL4) can stimulate TIB6 tumor growth even when VEGF is inhibited. We show that platelet-derived growth factor C (PDGF-C) is upregulated in TAFs from resistant tumors. PDGF-C-neutralizing antibodies blocked the angiogenesis induced by such TAFs in vivo, slowed the growth of EL4 and admixture (TAF-EL4 + TIB6) tumors, and exhibited additive effects with anti-VEGF-A antibodies. Hence, our data reveal an additional mechanism for TAF-mediated tumorigenesis and suggest that some tumors may overcome inhibition of VEGF-mediated angiogenesis through upregulation of PDGF-C.

MeSH terms

  • Animals
  • Antibodies / immunology
  • Antibodies / therapeutic use*
  • CD11b Antigen / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Separation
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology*
  • Cells, Cultured
  • Chemokine CXCL12 / metabolism
  • Disease Progression
  • Drug Resistance, Neoplasm / drug effects
  • Fibroblasts / metabolism*
  • Fibroblasts / pathology
  • Humans
  • Immunotherapy
  • Lymphokines / metabolism*
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Platelet-Derived Growth Factor / metabolism*
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / immunology*

Substances

  • Antibodies
  • CD11b Antigen
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Lymphokines
  • Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor A
  • platelet-derived growth factor C

Associated data

  • GEO/GSE13549