Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice

J Clin Invest. 2009 Dec;119(12):3613-25. doi: 10.1172/JCI38988. Epub 2009 Nov 16.

Abstract

Membrane-bound proteases have recently emerged as critical mediators of tumorigenesis, angiogenesis, and metastasis. However, the mechanisms by which they regulate these processes remain unknown. As the cell surface serine protease fibroblast activation protein (FAP) is selectively expressed on tumor-associated fibroblasts and pericytes in epithelial tumors, we set out to investigate the role of FAP in mouse models of epithelial-derived solid tumors. In this study, we demonstrate that genetic deletion and pharmacologic inhibition of FAP inhibited tumor growth in both an endogenous mouse model of lung cancer driven by the K-rasG12D mutant and a mouse model of colon cancer, in which CT26 mouse colon cancer cells were transplanted into immune competent syngeneic mice. Interestingly, growth of only the K-rasG12D-driven lung tumors was also attenuated by inhibition of the closely related protease dipeptidyl peptidase IV (DPPIV). Our results indicate that FAP depletion inhibits tumor cell proliferation indirectly, increases accumulation of collagen, decreases myofibroblast content, and decreases blood vessel density in tumors. These data provide proof of principle that targeting stromal cell-mediated modifications of the tumor microenvironment may be an effective approach to treating epithelial-derived solid tumors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Collagen / metabolism
  • Colonic Neoplasms / blood supply
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / prevention & control*
  • Female
  • Gelatinases / antagonists & inhibitors*
  • Gelatinases / deficiency
  • Gelatinases / genetics
  • Gelatinases / physiology
  • Genes, ras
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Membrane Proteins / antagonists & inhibitors*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Protease Inhibitors / pharmacology
  • Pyrrolidines / pharmacology
  • Serine Endopeptidases / deficiency
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / physiology
  • Stromal Cells / pathology
  • Transplantation, Isogeneic

Substances

  • 1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine
  • Membrane Proteins
  • Protease Inhibitors
  • Pyrrolidines
  • Collagen
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases
  • Adamantane