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Figure 3. Mechanisms of resistance to anti-angiogenic therapy. Hyperproduction of VEGFA is a consequence of the hypoxic status in the center of the tumor which activates HIF1A, a transcription factor that regulates VEGFA transcription. Overproduction of VEGFA can be blocked by monoclonal antibodies (bevacizumab, Beva) or a VEGF-trap (aflibercept, Afli). Alternatively, the signal can be blocked downstream of the dedicated receptor by small kinase inhibitors like regorafenib (Rego), which can also inhibit the TIE2 receptor, thus imposing a double anti-angiogenic blockade. In fact, both receptors are critical in stimulating the proliferation and migration of the endothelial cells, necessary for the formation of new vessels into and around the tumor mass. In particular, TIE2 receptor is regulated by ANGPT1 and 2, the former inducing signals involved in maturation and stabilization of blood vessels, whereas the latter blocks this signaling and triggers remodeling of vascular sprouts. Overproduction of ANGPT2 can drive a parallel neo-angiogenic signaling when VEGR-driven signaling is impeded by Beva-based therapy. In addition, another parallel neo-angiogenic pathway that can act as an escape route to VEGFA blockade is initiated by TGFB binding to a multimeric receptor formed by a TGFB2 dimer in complex with an activin receptor-like kinase 1 (ACVRL1) dimer.