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

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 overexpression 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.

journal_name

Int J Oncol

authors

Huang J,Bae JO,Tsai JP,Kadenhe-Chiweshe A,Papa J,Lee A,Zeng S,Kornfeld ZN,Ullner P,Zaghloul N,Ioffe E,Nandor S,Burova E,Holash J,Thurston G,Rudge J,Yancopoulos GD,Yamashiro DJ,Kandel JJ

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

79-87

issue

1

eissn

1019-6439

issn

1791-2423

journal_volume

34

pub_type

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