Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade

Jianzhong Huang, Jae O. Bae, Judy P. Tsai, Angela Kadenhe-Chiweshe, Joey Papa, Alice Lee, Shan Zeng, Z. Noah Kornfeld, Paivi Ullner, Nibal Zaghloul, Ella Ioffe, Sarah Nandor, Elena Burova, Jocelyn Holash, Gavin Thurston, John Rudge, George D. Yancopoulos, Darrell J. Yamashiro, Jessica J. Kandel

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Approval of the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab by the FDA in 2004 reflected the success of this vascular targeting strategy in extending survival in patients with advanced cancers. However, consistent with previous reports that experimental tumors can grow or recur during VEGF blockade, it has become clear that many patients treated with VEGF inhibitors will ultimately develop progressive disease. Previous studies have shown that disruption of VEGF signaling in tumors induces remodeling in surviving vessels, and link increased expression of angiopoietin-1 (Ang-1) with this process. However, overexpression of Ang-1 in different tumors has yielded divergent results, restricting angiogenesis in some systems while promoting it in others. These data raise the possibility that effects of Ang-1/Tie-2 may be context-dependent. Expression of an Ang-1 construct (Ang1*) did not significantly change tumor growth in our model prior to treatment, although vessels exhibited changes consistent with increased Tie-2 signaling. During inhibition of VEGF, however, both over expression of Ang1* and administration of an engineered Ang-1 agonist (Bow-Ang1) strikingly protected tumors and vasculature from regression. In this context, Ang-1/Tie-2 activation limited tumor hypoxia, increased vessel caliber, and promoted recruitment of mural cells. Thus, these studies support a model in which activation of Tie-2 is important for tumor and vessel survival when VEGF-dependent vasculature is stressed. Understanding such mechanisms of adaptation to this validated form of therapy may be important in designing regimens that make the best use of this approach.

Original languageEnglish (US)
Pages (from-to)79-87
Number of pages9
JournalInternational journal of oncology
Volume34
Issue number1
DOIs
StatePublished - 2009
Externally publishedYes

Keywords

  • Angiogenesis
  • Angiopoietin-1
  • Tie-2
  • Tumor growth
  • Vascular remodeling
  • VEGF

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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