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

SIMPLE SUMMARY: In order for solid tumors to grow, they need to develop new blood vessels in order to support their increasing metabolic requirements. To facilitate the novel vessel formation, the tumor initiates an aggressive pro-angiogenic program. As a result of the aggressive angiogenesis, blood vessels form very rapidly and are often malformed and dysfunctional. There is a reduction in perfusion to the tumor, and often the tumors exhibit significant areas of tumor hypoxia. This review paper discusses the pro-tumorigenic environment induced by tumor hypoxia and how this can be targeted through normalization of the tumor vasculature. Here, we review tumor angiogenesis, the development of a hypoxic phenotype, and how this contributes to sustained tumorigenesis and resistance to therapy. We further discuss the potential of vascular normalization to reduce tumor hypoxia and facilitate uptake and efficacy of a variety of therapies. 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.