Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors

Abstract

Function-blocking antibodies to VEGF receptors R1 and R2 were used to probe their roles in controlling angiogenesis in a mouse model of pancreatic islet carcinogenesis. Inhibition of VEGFR2 but not VEGFR1 markedly disrupted angiogenic switching, persistent angiogenesis, and initial tumor growth. In late-stage tumors, phenotypic resistance to VEGFR2 blockade emerged, as tumors regrew during treatment after an initial period of growth suppression. This resistance to VEGF blockade involves reactivation of tumor angiogenesis, independent of VEGF and associated with hypoxia-mediated induction of other proangiogenic factors, including members of the FGF family. These other proangiogenic signals are functionally implicated in the revascularization and regrowth of tumors in the evasion phase, as FGF blockade impairs progression in the face of VEGF inhibition.

Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib

“…These factors may have an important role in the induction of tumour angiogenesis and may also be involved in altering the responsiveness of tumour blood vessels to inhibitors of the VEGF signalling axis (Bergers and Hanahan, 2008). In support of this latter concept, FGF2 is upregulated in a mouse tumour model of acquired resistance to DC101 (a VEGFR2 inhibitory antibody) and inhibition of FGF2 in combination with DC101 led to improved anti-tumour responses (Casanovas et al, 2005). Moreover, inhibition of PLGF or PDGF has been reported to enhance the anti-tumour efficacy of VEGF pathway inhibitors in some murine tumour models (Bergers et al, 2003;Fischer et al, 2007;Crawford et al, 2009).…”

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

“…Although our observations may depend on intrinsic characteristics of C6 glioma and sorafenib, spatially heterogeneous treatment response was also noted in several previous studies. For example, the tumor periphery exhibited maintenance of high BV and vascular integrity against monoclonal antibody to VEGF/VEGFR or vessel‐targeting treatment 38, 39, 40. Therefore, preservation of inherent vascular phenotypes against antiangiogenic treatment in the tumor periphery can be regarded as a process in the tumor that potentiates drug resistance.…”

Can we develop effective combination antiangiogenic therapy for patients with hepatocellular carcinoma?

“…Effective antiangiogenic therapy works by creating a hypoxic condition devoid of nutrients for sustained cellular growth/survival. However, intratumoral hypoxia leads to the induction of compensatory pathways that mediate resistance at the levels of the tumor blood vessels, microenvironment, and tumor epithelial cells [17, 18]. In preclinical models, the hypoxia-inducible factors, HIF-1 α and HIF-2 α , have been shown to be major mediators of reactive resistance [21, 42] (Fig.…”

“…In combination with antiangiogenic agents, inhibiting both HIF-1 α and HIF-2 α would further disrupt tumorigenesis through two potential mechanisms. The first mechanism of synergy is by modulation of additional angiogenic pathways that complement those affected by the currently available antiangiogenic agents [18]. We recently reported that inhibition of HIF-1 α and HIF-2 α in cancer cells improved the antiangiogenic effect of sunitinib due to the inhibition of the proangiogenic factor, ANGPTL4, and induction of the antiangiogenic factor, TSP1 [42].…”