TY - JOUR
T1 - Angiopoietin-1/Tie-2 activation contributes to vascular survival and tumor growth during VEGF blockade
AU - Huang, Jianzhong
AU - Bae, Jae O.
AU - Tsai, Judy P.
AU - Kadenhe-Chiweshe, Angela
AU - Papa, Joey
AU - Lee, Alice
AU - Zeng, Shan
AU - Kornfeld, Z. Noah
AU - Ullner, Paivi
AU - Zaghloul, Nibal
AU - Ioffe, Ella
AU - Nandor, Sarah
AU - Burova, Elena
AU - Holash, Jocelyn
AU - Thurston, Gavin
AU - Rudge, John
AU - Yancopoulos, George D.
AU - Yamashiro, Darrell J.
AU - Kandel, Jessica J.
PY - 2009
Y1 - 2009
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Angiopoietin-1
KW - Tie-2
KW - Tumor growth
KW - VEGF
KW - Vascular remodeling
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U2 - 10.3892/ijo_00000131
DO - 10.3892/ijo_00000131
M3 - Article
C2 - 19082480
AN - SCOPUS:60749124285
SN - 1019-6439
VL - 34
SP - 79
EP - 87
JO - International journal of oncology
JF - International journal of oncology
IS - 1
ER -