VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression

Cancer Res. 2012 Aug 15;72(16):3912-8. doi: 10.1158/0008-5472.CAN-11-4058. Epub 2012 Jun 12.

Abstract

VEGF/vascular permeability factor (VEGF/VPF or VEGF-A) is a pivotal driver of cancer angiogenesis that is a central therapeutic target in the treatment of malignancy. However, little work has been devoted to investigating functions of VEGF that are independent of its proangiogenic activity. Here, we report that VEGF produced by tumor cells acts in an autocrine manner to promote cell growth through interaction with the VEGF receptor neuropilin-1 (NRP-1). Reducing VEGF expression by tumor cells induced a differentiated phenotype in vitro and inhibited tumor forming capacity in vivo, independent of effects on angiogenesis. Autocrine activation of tumor cell growth was dependent on signaling through NRP-1, and Ras was determined to be a critical effector signaling molecule downstream of NRP-1. Our findings define a novel function for VEGF in dedifferentiation of tumor cells expanding its role in cancer beyond its known proangiogenic function.

Publication types

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

MeSH terms

  • Animals
  • Breast Neoplasms / blood supply
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology*
  • Carcinoma, Renal Cell / blood supply
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology*
  • Cell Dedifferentiation / physiology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Female
  • Gene Knockdown Techniques
  • Humans
  • Kidney Neoplasms / blood supply
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology*
  • MCF-7 Cells
  • Mice
  • Mice, Nude
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Neuropilin-1 / genetics
  • Neuropilin-1 / metabolism
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / genetics
  • Signal Transduction
  • Transfection
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*

Substances

  • RNA, Small Interfering
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Neuropilin-1