Vascular Normalization by Vascular Endothelial Growth Factor Receptor 2 Blockade Induces a Pressure Gradient Across the Vasculature and Improves Drug Penetration in Tumors

Abstract

Elevated interstitial fluid pressure, a hallmark of solid tumors, can compromise the delivery of therapeutics to tumors. Here we show that blocking vascular endothelial growth factor (VEGF) signaling by DC101 (a VEGF-receptor-2 antibody) decreases interstitial fluid pressure, not by restoring lymphatic function, but by producing a morphologically and functionally "normalized" vascular network. We demonstrate that the normalization process prunes immature vessels and improves the integrity and function of the remaining vasculature by enhancing the perivascular cell and basement membrane coverage. We also show that DC101 induces a hydrostatic pressure gradient across the vascular wall, which leads to a deeper penetration of molecules into tumors. Thus, vascular normalization may contribute to the improved survival rates in tumor-bearing animals and in colorectal carcinoma patients treated with an anti-VEGF antibody in combination with cytotoxic therapies.

Potential autocrine function of vascular endothelial growth factor in head and neck cancer via vascular endothelial growth factor receptor-2

“…A fundamental approach to inhibit angiogenesis during tumorigenesis is the disruption of VEGF/VEGFR-2 pathway. 41 This could suppress tumor growth by limiting their blood supply, by changing the morphology, wall structure and function of tumor vasculature to a more normal fashion, 42 and thus improving drug penetration in tumors, and also by blocking VEGF autocrine pathway and thus reducing uncontrolled neoplastic cell proliferation.…”

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

“…Twelve days after bevacizumab therapy alone, the tumor interstitial fluid pressure (IFP) was consistently decreased, particularly in patients with high baseline values [45,46]. This suggests that in human tumors, similar to mouse models [47,48], the tumor microenvironment is normalized by the reduction of the excess abnormal vasculature and is potentially sensitized to subsequent cytotoxic therapy.…”

Transvascular and interstitial transport in rat hepatocellular carcinomas: Dynamic contrast‐enhanced MRI assessment with low‐ and high‐molecular weight agents

“…The effect of antiangiogenic and antivascular treatments on perfusion and transvascular and interstitial transport is complex and depends on the tumor, the type and dose of the treatment, and the timing after the start of the treatment (7). The perfusion may be decreased by destruction of the angiogenic vessels (8) or it may be increased by dilation of the remaining vessels (9). The decrease of vessel permeability caused by antiangiogenic treatments may increase rather than decrease the transvascular and interstitial transport of macromolecules by decreasing the elevated interstitial pressure related to the leaky endothelial vessels (9).…”

“…The perfusion may be decreased by destruction of the angiogenic vessels (8) or it may be increased by dilation of the remaining vessels (9). The decrease of vessel permeability caused by antiangiogenic treatments may increase rather than decrease the transvascular and interstitial transport of macromolecules by decreasing the elevated interstitial pressure related to the leaky endothelial vessels (9). As antiangiogenic treatments may have different effects on tumor perfusion and transvascular/interstitial transport, it is important that magnetic resonance imaging (MRI)-derived kinetic model and parameters be able to assess separately these two parameters.…”