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ANGPTL4 is a secreted tumor suppressor that inhibits angiogenesis

E Okochi-Takada1, N Hattori1, T Tsukamoto2

  • 1Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.

Oncogene
|May 21, 2013
PubMed

Insights

Angiopoietin-like 4 (ANGPTL4) is a secreted tumor suppressor. Its inactivation promotes gastric cancer development and angiogenesis, highlighting its therapeutic potential.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Extracellular tumor suppressors offer therapeutic advantages, yet few are identified.
  • Angiopoietin-like 4 (ANGPTL4), a secreted glycoprotein, has roles in metabolism and angiogenesis but its function in cancer is unclear.
  • ANGPTL4 is known to be epigenetically silenced in human cancers.

Purpose of the Study:

  • To investigate the role of angiopoietin-like 4 (ANGPTL4) in cancer development and progression.
  • To determine if ANGPTL4 acts as a tumor suppressor and its mechanism of action.
  • To explore the genetic and epigenetic alterations of ANGPTL4 in human gastric cancers.

Main Methods:

  • Analysis of ANGPTL4 genetic mutations (deletion) and epigenetic modifications (hypermethylation) in gastric cancer tissues.
  • Forced expression of wild-type and mutant ANGPTL4 in vivo and in vitro.
  • Assessment of tumor growth, angiogenesis, and endothelial cell function.
  • Investigation of signaling pathways, including ERK signaling.

Main Results:

  • A deletion mutation in the N-terminal coiled-coil domain of ANGPTL4 was identified in human gastric cancers.
  • Hypermethylation of ANGPTL4 promoter CpG islands was observed.
  • Forced expression of wild-type ANGPTL4 suppressed tumor growth and angiogenesis in vivo.
  • Tumor-derived ANGPTL4 inhibited endothelial cell proliferation and vascular tube formation, partly via ERK signaling suppression.

Conclusions:

  • ANGPTL4 functions as a secreted tumor suppressor that is inactivated by genetic and epigenetic alterations in gastric cancer.
  • ANGPTL4 suppresses tumor angiogenesis and endothelial cell function.
  • Restoring ANGPTL4 function may represent a potential therapeutic strategy for cancer.

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