Endothelial Cells Require CD98 for Efficient Angiogenesis-Brief Report

Arterioscler Thromb Vasc Biol. 2016 Nov;36(11):2163-2166. doi: 10.1161/ATVBAHA.116.308335. Epub 2016 Sep 29.

Abstract

Objective: CD98 regulates integrin signaling and is critical for tumor cell proliferation. It is also expressed on endothelial cells (EC), but its role in angiogenesis is unclear.

Approach and results: We used specific genetic targeting and antibody blockade approaches to examine the function of CD98 in EC proliferation, blood vessel growth, and tumor angiogenesis. It is upregulated on angiogenic ECs, and EC-specific deletion of CD98 in mice inhibited tumor growth, retinal angiogenesis, and EC proliferation. Reconstitution with CD98 mutants showed that integrin and CD98 interaction is necessary for EC survival and growth. Moreover, anti-CD98 treatment inhibited vessel formation and reversed EC-assisted tumor growth.

Conclusions: Our findings demonstrate a requirement for CD98 in EC growth and suggest that CD98-specific reagents could have a dual anticancer effect: directly by inhibiting tumor cell proliferation and indirectly by preventing tumor angiogenesis.

Keywords: angiogenesis inhibitors; cell proliferation; endothelial cell; integrins.

Publication types

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

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antibodies / pharmacology
  • Carcinoma, Lewis Lung / blood supply
  • Carcinoma, Lewis Lung / drug therapy
  • Carcinoma, Lewis Lung / genetics
  • Carcinoma, Lewis Lung / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Female
  • Fusion Regulatory Protein 1, Heavy Chain / genetics
  • Fusion Regulatory Protein 1, Heavy Chain / immunology
  • Fusion Regulatory Protein 1, Heavy Chain / metabolism*
  • Genotype
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / immunology
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Human Umbilical Vein Endothelial Cells / transplantation
  • Humans
  • Integrins / metabolism
  • Male
  • Melanoma, Experimental / blood supply
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / metabolism*
  • Mice, Knockout
  • Neovascularization, Pathologic*
  • Neovascularization, Physiologic* / drug effects
  • Phenotype
  • Phosphorylation
  • Retinal Neovascularization / drug therapy
  • Retinal Neovascularization / genetics
  • Retinal Neovascularization / metabolism*
  • Retinal Neovascularization / pathology
  • Signal Transduction
  • Time Factors
  • Tumor Burden
  • Vascular Endothelial Growth Factor A / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

  • Angiogenesis Inhibitors
  • Antibodies
  • Fusion Regulatory Protein 1, Heavy Chain
  • Integrins
  • Slc3A2 protein, mouse
  • Vascular Endothelial Growth Factor A
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2