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.

Angiogenesis: A Pivotal Therapeutic Target in the Drug Development of Gynecologic Cancers

“…Agents targeting the angiopoietin pathway, such as trebananib, and the TGF-ß pathway, such as tasisulam, have been met with limited clinical success [ 85 , 86 , 87 , 120 ]. The normalization of tumor vascularization through the upregulating of thrombospondin-1and the promotion of smooth muscle cell proliferation and migration in conjunction with EC apoptosis could potentially regulate therapeutic intratumoral drug delivery, enhancing efficacy [ 121 , 122 ]. Drug development in this area appears promising, but remains in pre-clinical stages at present [ 123 ].…”

Lymphatic Endothelial Markers and Tumor Lymphangiogenesis Assessment in Human Breast Cancer

“…In peritumoral stroma, lymphatic vessels appear to be inflamed and dilated, which serve as the functional route for cancer-cell dissemination ( Figure 4 a,b). By contrast, the existence of lymphatic vessels in intratumoral areas is ambiguous, and the majority of the lymphatic vessels in intratumoral areas are sparse, dysfunctional, collapsed vessels with a long narrow or atretic shape ( Figure 4 c), which is unfavorable for lymph draining or cell migration [ 90 ]. These destructing lymphatics may contribute to increasing the compressive stress within tumor areas [ 91 , 92 ].…”

“…For example, Kruger et al [ 100 ] showed that a high baseline microvessel density was significantly associated with the response to bevacizumab. However, tumor vasculatures are dysfunctional, leading to immunosuppression and therapy resistance in the vast majority of cases, and normalizing the tumor vasculature can optimize drug uptake [ 90 ].…”

Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer

“…Anti-angiogenic therapies can normalize tumor vasculature, uniformly increase oxygen delivery and reverse the hypoxic areas of the tumor. This allows for better uptake and distribution of therapeutic drugs to the tumor ( 203 ). Many anti-angiogenic therapies work by inhibiting VEGF, either by directly binding to VEGF or inhibiting the VEGF receptor.…”