Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor

Rakesh K. Jain*, Nina Safabakhsh, Axel Sckell, Yi Chen, Ping Jiang, Laura Benjamin, Fan Yuan, Eli Keshet

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

335 Scopus citations

Abstract

The sequence of events that leads to tumor vessel regression and the functional characteristics of these vessels during hormone-ablation therapy are not known. This is because of the lack of an appropriate animal model and monitoring technology. By using in vivo microscopy and in situ molecular analysis of the androgen-dependent Shionogi carcinoma grown in severe combined immunodeficient mice, we show that castration of these mice leads to tumor regression and a concomitant decrease in vascular endothelial growth factor (VEGF) expression. Androgen withdrawal is known to induce apoptosis in Shionogi tumor cells. Surprisingly, tumor endothelial cells begin to undergo apoptosis before neoplastic cells, and rarefaction of tumor vessels precedes the decrease in tumor size. The regressing vessels begin to exhibit normal phenotype, i.e., lower diameter, tortuosity, vascular permeability, and leukocyte adhesion. Two weeks after castration, a second wave of angiogenesis and tumor growth begins with a concomitant increase in VEGF expression. Because human tumors often relapse following hormone-ablation therapy, our data suggest that these patients may benefit from combined anti-VEGF therapy.

Original languageEnglish
Pages (from-to)10820-10825
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number18
DOIs
StatePublished - 1 Sep 1998

Keywords

  • Permeability
  • Vascular density
  • Vascular regression

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