Requirement for sphingosine 1-phosphate receptor-1 in tumor angiogenesis demonstrated by in vivo RNA interference. Academic Article uri icon

Overview

abstract

  • Angiogenesis, or new blood vessel formation, is critical for the growth and spread of tumors. Multiple phases of this process, namely, migration, proliferation, morphogenesis, and vascular stabilization, are needed for optimal tumor growth beyond a diffusion-limited size. The sphingosine 1-phosphate (S1P) receptor-1 (S1P(1)) is required for stabilization of nascent blood vessels during embryonic development. Here we show that S1P(1) expression is strongly induced in tumor vessels. We developed a multiplex RNA interference technique to downregulate S1P(1) in mice. The small interfering RNA (siRNA) for S1P(1) specifically silenced the cognate transcript in endothelial cells and inhibited endothelial cell migration in vitro and the growth of neovessels into subcutaneous implants of Matrigel in vivo. Local injection of S1P(1) siRNA, but not a negative control siRNA, into established tumors inhibited the expression of S1P(1) polypeptide on neovessels while concomitantly suppressing vascular stabilization and angiogenesis, which resulted in dramatic suppression of tumor growth in vivo. These data suggest that S1P(1) is a critical component of the tumor angiogenic response and argue for the utility of siRNA technology in antiangiogenic therapeutics.

publication date

  • October 1, 2004

Research

keywords

  • Neoplasms
  • Neovascularization, Pathologic
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Lysosphingolipid

Identity

PubMed Central ID

  • PMC522258

Scopus Document Identifier

  • 9644252866

Digital Object Identifier (DOI)

  • 10.1172/JCI22716

PubMed ID

  • 15489955

Additional Document Info

volume

  • 114

issue

  • 8