Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade

Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade

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Angiopoietin-2 (ANG2/ANGPT2) is a context-dependent TIE2 receptor agonist/antagonist and proangiogenic factor.Although ANG2 neutralization improves tumor angiogenesis and growth inhibition by vascular endothelial growth factor (VEGF)-A signaling blockade, the mechanistic underpinnings of such therapeutic benefits remain poorly explored.We employed late-stage RIP1-Tag2 pancreatic neuroendocrine tumors (PNETs) and MMTV-PyMT mammary adenocarcinomas, which develop resistance pickudi to VEGF receptor 2 (VEGFR2) blockade.

We found that VEGFR2 inhibition upregulated ANG2 and vascular TIE2 and enhanced infiltration by TIE2-expressing macrophages in the PNETs.Dual ANG2/VEGFR2 blockade suppressed revascularization and progression in most of the PNETs, whereas it had only minor additive effects in the mammary tumors, which did not upregulate ANG2 upon VEGFR2 inhibition.ANG2/VEGFR2 blockade did not elicit increased PNET invasion and metastasis, although it exacerbated tumor hypoxia and hematopoietic cell infiltration.

These findings suggest that evasive tumor resistance to anti-VEGFA therapy may involve the wavertree and london cosmopolitan candle adaptive enforcement of ANG2-TIE2 signaling, which can be reversed by ANG2 neutralization.