Abstract
Our research has identified several examples in which reduced VEGF-A binding to deficient vascular extracellular matrix leads to deficits in tumor vascularization and tumor growth: (1) germline ablation of collagen VI in the stroma of intracranial B16F10 melanomas; (2) knockdown of the Tks5 scaffolding protein in MDA-MB-231 mammary tumor cells; (3) germline ablation of NG2 proteoglycan in the stroma of MMTV-PyMT mammary tumors; and (4) myeloid-specific ablation of NG2 in the stroma of intracranial B16F10 melanomas. Tumor hypoxia is increased in each of the four types of experimental mice, accompanied by increases in total VEGF-A. However, while VEGF-A is highly associated with tumor blood vessels in control mice, it is much more diffusely distributed in tumors in all four sets of experimental mice, likely due to reduced extent of the vascular extracellular matrix. In parallel to lost VEGF-A localization, tumor vessels in each case have smaller diameters and are leakier than tumor vessels in control mice. Tumor growth is decreased as a result of this poor vascular function. The fact that the observed vascular changes occur in the absence of alterations in vascular density suggests that examination of vessel structure and function is more useful than vascular density for understanding the importance of angiogenesis in tumor progression.
Highlights
Microvessels are primarily composed of three elements: endothelial cells, pericytes, and the vascular basement membrane
Collagen VI is a rather unique collagen species that provides a link between cell surface receptors, such as integrins [17] and the nerve-glia antigen-2 (NG2) proteoglycan [18], and fibrillar collagens such as collagens I and IV that are involved in basement membrane assembly [19,20]
It is important to note that the observed changes in vessel structure and function occurred in the absence of changes in tumor vessel density, a phenomenon that was seen in each of the other three tumor models. This suggests that examination of tumor vessel structure and function can be more valuable than vessel density in understanding the role of the vasculature in tumor progression. Using both intracranial and mammary tumors, our lab has identified several examples in which diminished assembly of the vascular basement membrane is linked to additional deficits in the structure and function of tumor blood vessels
Summary
Microvessels are primarily composed of three elements: endothelial cells, pericytes, and the vascular basement membrane. The three microvascular components are not independent entities, but instead interact in complex ways to determine vessel development, maturation, maintenance, and function [1,2,3,4,5] These studies from our lab and others make it clear that assembly of the vascular basement membrane depends on cooperation between pericytes and endothelial cells, and that the properties of the two vascular cell populations rely in turn on their interaction with the basement membrane. Cancers 2017, 9, 97 in which reduced VEGF-A binding to deficient vascular extracellular matrix leads to deficits in tumor vascularization In these examples, different mechanisms are responsible for aberrant assembly of the vascular extracellular matrix and for associated alterations in the properties of pericyte and endothelial cells. We have seen changes in tumor vascularization and growth that appear to result from relatively direct effects on assembly and processing of the vascular extracellular matrix
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