Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

Abstract

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area.

Keywords: angiogenesis; drug delivery; hypoxia; therapy resistance; vascular normalization.

Figure 1

Hypoxia induced by the growing tumor mass triggers an “angiogenic switch” within the tumor microenvironment, resulting in a crude version of angiogenesis.

Figure 2

Tumor hypoxia activates several tumorigenic processes. Tumor vasculature has altered morphology, with reduced pericyte coverage. The immature tumor vessels are characterized by blind end shunts, torturous pathway, sacculations, decreased luminal size, and increased fenestrations. Excessively fenestrated vessels allow for fluid extravasation and increased interstitial fluid pressure (IFP) and facilitate intravasation and migration of metastatic tumor cells. Elevated IFP and disrupted tissue perfusion contribute to areas of acute and chronic hypoxia, which can activate numerous pro-tumorigenic processes.