Nuclear receptor COUP-TFII controls pancreatic islet tumor angiogenesis by regulating vascular endothelial growth factor/vascular endothelial growth factor receptor-2 signaling

Cancer Res. 2010 Nov 1;70(21):8812-21. doi: 10.1158/0008-5472.CAN-10-0551. Epub 2010 Oct 26.

Abstract

The significance of angiogenesis in cancer biology and therapy is well established. In this study, we used the prototypical RIP-Tag model of multistage pancreatic islet tumorigenesis to show that the nuclear receptor COUP-TFII is essential to regulate the balance between pro- and anti-angiogenic molecules that influence the angiogenic switch in cancer. Conditional ablation of COUP-TFII in the tumor microenvironment severely compromised neoangiogenesis and lymphangiogenesis during pancreatic tumor progression and metastasis. We found that COUP-TFII plays a cell-autonomous role in endothelial cells to control blood vessel sprouting by regulating cell proliferation and migration. Mechanistic investigations revealed that COUP-TFII suppressed vascular endothelial growth factor (VEGF)/VEGF receptor-2 (VEGFR-2) signaling by transcriptionally repressing the expression of VEGFR-1, thereby curtailing a central angiogenic driver of vascular growth. Taken together, our results implicate COUP-TFII as a critical factor in tumor angiogenesis through regulation of VEGF/VEGFR-2 signaling, suggesting COUP-TFII as a candidate target for antiangiogenic therapy.

Publication types

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

MeSH terms

  • Animals
  • Blotting, Western
  • COUP Transcription Factor II / antagonists & inhibitors
  • COUP Transcription Factor II / physiology*
  • Cell Adhesion
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Endothelium, Lymphatic / cytology
  • Endothelium, Lymphatic / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism
  • Female
  • GTPase-Activating Proteins / physiology
  • Humans
  • Immunoenzyme Techniques
  • Infant, Newborn
  • Integrases / metabolism
  • Lymphatic Metastasis
  • Male
  • Mice
  • Mice, Transgenic
  • Neovascularization, Pathologic / pathology*
  • Pancreatic Neoplasms / blood supply
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / prevention & control
  • Proteins / physiology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • RNA, Untranslated
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction*
  • Umbilical Veins / cytology
  • Umbilical Veins / metabolism
  • Vascular Endothelial Growth Factor A / physiology*
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / genetics*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • COUP Transcription Factor II
  • GTPase-Activating Proteins
  • Gt(ROSA)26Sor non-coding RNA, mouse
  • Nr2f2 protein, mouse
  • Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • RNA, Untranslated
  • Ralbp1 protein, mouse
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • Cre recombinase
  • Integrases