Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth

J Clin Invest. 2003 Jul;112(1):67-75. doi: 10.1172/JCI16645.

Abstract

Although the renin angiotensin system (RAS) is a major regulator of vascular homeostasis, the role of the RAS in tumor angiogenesis is little understood. Here we show that host angiotensin II (ATII) type 1 (AT1) receptor plays an important role in angiogenesis and growth of tumor cells engrafted in mice. Subcutaneous B16-F1 melanoma-induced angiogenesis as assessed by tissue capillary density and microangiography was prominent in WT mice but was reduced in AT1a receptor-deficient (AT1a-/-) mice. Consequently, tumor growth rate was significantly slower, and the mouse survival rate was greater, in AT1a-/- mice than in WT mice. Tumor growth was also reduced in WT mice treated with TCV-116, a selective blocker of AT1 receptor. Because the beta-galactosidase gene was inserted into the AT1a gene locus in AT1a-/- mice, the site of beta-galactosidase expression represents the AT1a receptor expression in these mutant mice. In tumor-implanted AT1a-/- mice, the major site of the beta-galactosidase expression was macrophages in tissues surrounding tumors. Moreover, the number of infiltrated macrophages was significantly lower in AT1a-/- mice than in WT mice, and double-immunofluorescence staining revealed that these macrophages expressed VEGF protein intensively. Therefore, the host ATII-AT1 receptor pathway supports tumor-associated macrophage infiltration, which results in enhanced tissue VEGF protein levels. The host ATII-AT1 receptor pathway thereby plays important roles in tumor-related angiogenesis and growth in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology
  • Biphenyl Compounds / pharmacology
  • Cyclohexanes
  • Endothelial Growth Factors / analysis
  • Intercellular Signaling Peptides and Proteins / analysis
  • Lymphokines / analysis
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms, Experimental / blood supply*
  • Neoplasms, Experimental / pathology
  • Neovascularization, Pathologic / etiology*
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin / analysis
  • Receptors, Angiotensin / physiology*
  • Sesquiterpenes / pharmacology
  • Tetrazoles*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Benzimidazoles
  • Biphenyl Compounds
  • Cyclohexanes
  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Receptor, Angiotensin, Type 1
  • Receptors, Angiotensin
  • Sesquiterpenes
  • Tetrazoles
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • candesartan cilexetil
  • O-(Chloroacetylcarbamoyl)fumagillol