VEGF signaling inhibitors: More pro-apoptotic than anti-angiogenic

Abstract

The vascular endothelial growth factor (VEGF) family of polypeptide growth factors regulates a family of VEGF receptor (VEGFR) tyrosine kinases with pleiotropic downstream effects. Angiogenesis is the best known of these effects, but additional VEGF-dependent actions include increased vascular permeability, paracrine/autocrine growth factor release, enhancement of cell motility, and inhibition of apoptosis. In theory, therapeutic inhibition of angiogenesis should reduce tumor perfusion and thus increase tumor hypoxia and chemoresistance, but in clinical practice the VEGF antibody bevacizumab acts as a broad-spectrum chemosensitizer. Since VEGFR expression occurs in many tumor types, such chemosensitization is more readily explained by direct inhibition of tumor cell survival signals than by indirect stromal/vascular effects. The emerging model of anti-VEGF drug action being mediated primarily by tumoral (as distinct from endothelial) VEGFRs has clinically important implications for optimizing the anti-metastatic efficacy of this expanding drug class.

Association of −2549 Insertion/Deletion Polymorphism of Vascular Endothelial Growth Factor with Breast Cancer in North Indian Patients

“…The actions of the VEGF family has been reported to be crucial for tumor growth and metastasis as tumors cannot grow beyond the initial size without establishment of a blood supply for acquiring nutrients and carrying away debris (Roy et al, 2006;Roskoski, 2007). It has been reported that VEGF contributes to cancer development by promoting cell growth and enhancing cell survival (Byrne et al, 2005;Takahashi and Shibuya, 2005;Breen, 2007;Epstein, 2007). Women with advanced breast cancer who received anti-angiogenesis therapy showed improvement in outcome (Schneider and Sledge, 2007).…”

Phase 1‐2 trial of PTK787/ZK222584 combined with intravenous doxorubicin for treatment of patients with advanced hepatocellular carcinoma

“…Bevacizumab binds VEGF with high affinity, 24 thereby inhibiting tumor growth, peregrine/anticrime growth factor release, and metastasis. 25 Moreover, it may enhance chemotherapeutic agent delivery to the tumor by normalizing tumor vasculature, 26 decreasing the elevated interstitial pressure in the tumor, and increasing vascular permeability. 25 Bevacizumab as a single agent or in combination with other agents has shown initial encouraging activity in treating advanced HCC.…”

“…25 Moreover, it may enhance chemotherapeutic agent delivery to the tumor by normalizing tumor vasculature, 26 decreasing the elevated interstitial pressure in the tumor, and increasing vascular permeability. 25 Bevacizumab as a single agent or in combination with other agents has shown initial encouraging activity in treating advanced HCC. In the study conducted by Siegel et al, among 46 enrolled patients with locally advanced HCC, singleagent bevacizumab achieved a 13% RR, 65% of patients were progression-free at 6 months, 27 and the median time to tumor progression was 6.9 months.…”

Management of Hepatocellular Carcinoma: An Update at the Start of 2014

“…VEGF as central mediator of angiogenesis is frequently expressed in HCC [34] and VEGF levels correlate with angiogenic activity, tumor progression and poor prognosis [35][36][37]. Its effects are mediated via its interaction with tyrosine kinase receptors, namely VEGFR-1 [Flt-1], VEGFR-2 [Flk-1/ Kdr] and VEGFR-3 [Flt-4], which are located on endothelial cells [37]. Angiogenesis and particularly VEGFR signaling can be targeted either by the monoclonal antibody bevacizumab or by inhibiting downstream intracellular tyrosine kinases by small molecules such as sorafenib or sunitinib.…”