Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade.
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.
Huang
Jianzhong
J
Department of Surgery, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Bae
Jae-O
JO
Tsai
Judy P
JP
Kadenhe-Chiweshe
Angela
A
Papa
Joey
J
Lee
Alice
A
Zeng
Shan
S
Kornfeld
Z Noah
ZN
Ullner
Paivi
P
Zaghloul
Nibal
N
Ioffe
Ella
E
Nandor
Sarah
S
Burova
Elena
E
Holash
Jocelyn
J
Thurston
Gavin
G
Rudge
John
J
Yancopoulos
George D
GD
Yamashiro
Darrell J
DJ
Kandel
Jessica J
JJ
D042683:Angiopoietin-1 / Q000235:genetics*; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000473:pathology*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D042787:Receptor, TIE-2 / Q000235:genetics*; D012512:Sarcoma, Ewing / Q000098:blood supply* / Q000473:pathology; D014162:Transfection; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2