Fibroblast activation protein regulates tumor-associated fibroblasts and epithelial ovarian cancer cells

Int J Oncol. 2012 Aug;41(2):541-50. doi: 10.3892/ijo.2012.1475. Epub 2012 May 14.

Abstract

The fibroblast activation protein (FAP) is a cell surface serine protease which has emerged as a specific marker of tumor-associated fibroblasts (TAFs). FAP has been shown to have both in vitro dipeptidyl peptidase and collagenase activity. However, the biological function of FAP in the tumor microenvironment is largely unknown. In this study, we first show that TAFs isolated from ovarian cancer samples have the characteristics of stem cells. To explore the functional role of FAP, the protein was silenced by siRNA lentiviral vector transfection. FAP silencing inhibited the growth of TAFs in vitro, accompanied with cell cycle arrest at the G2 and S phase in TAFs. FAP silencing also reduced the stem cell marker gene expression in TAFs. SKOV3 cells do not express FAP. Although FAP-silenced SKOV3 cells induced ovarian tumors, the rate of tumor growth was significantly decreased, as shown in the xenograft mouse model. TAF phenotypes in the xenograft tumor tissues were further assayed by immunohistochemistry. The expression of TAF markers, including fibroblast-specific protein, FAP, smooth muscle actin, desmin, vascular endothelial growth factor and fibroblast growth factor was decreased in the tumor stroma induced by FAP-silenced SKOV3 cells. In conclusion, FAP is an important regulator of the microenvironment in tumor formation and targeting FAP is a potential therapeutic strategy to combat ovarian cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormal Karyotype
  • Animals
  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Carcinoma, Ovarian Epithelial
  • Cell Shape
  • Chromosome Aberrations
  • Endopeptidases
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / physiology
  • G2 Phase Cell Cycle Checkpoints
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Gene Expression
  • Gene Knockdown Techniques
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasm Transplantation
  • Neoplasms, Glandular and Epithelial / pathology*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / physiology
  • Neovascularization, Pathologic
  • Ovarian Neoplasms / pathology*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Tumor Burden
  • Tumor Cells, Cultured
  • Tumor Microenvironment

Substances

  • Antigens, Differentiation
  • Membrane Proteins
  • RNA, Small Interfering
  • Endopeptidases
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases