PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment.
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.
Crawford
Yongping
Y
Genentech Inc, 1 DNA Way, South San Francisco, CA 94080, USA.
Kasman
Ian
I
Yu
Lanlan
L
Zhong
Cuiling
C
Wu
Xiumin
X
Modrusan
Zora
Z
Kaminker
Josh
J
Ferrara
Napoleone
N
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000627:therapeutic use*; D039481:CD11b Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007167:Immunotherapy; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology*
D000906:Antibodies; D039481:CD11b Antigen; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C411423:platelet-derived growth factor C