Chapter 12 - Melanoma Progression in the Brain: Role of Pericytes, the Basal Lamina, and Endothelial Cells in Tumor Vascularization

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Pericytes (mural cells), the vascular basal lamina, and endothelial cells are the primary components of microvessels in most tissues, including tumors. These components are not independent entities, but interact in complex ways to determine microvessel morphogenesis, maturation, and maintenance. We have used B16F10 melanomas growing in C57Bl/6 mouse brain as a format for evaluating the contributions of pericytes, endothelial cells, and the basal lamina to tumor vessel development and function. Genetic ablations of the NG2 proteoglycan and collagen VI were used to perturb the functions of pericytes and the basal lamina, respectively, as a means of assessing loss of vascular structure and function. In addition to determining molecular details of vessel structure and function, tumor progression was used as an overall readout of vascular performance. Although the absence of NG2 proteoglycan from pericytes did not affect the abundance of blood vessels or overall numbers of pericytes and endothelial cells, quantifiable deficits were found in pericyte coverage of endothelial cells, maturation of pericytes and endothelial cells, and assembly of the basal lamina. These structural changes resulted in significant changes in tumor vessel patency and leakiness, accompanied by increased tumor hypoxia and diminished tumor growth. In reducing deposition of the basal lamina, ablation of collagen VI did not alter pericyte investment of endothelial cells, but still diminished the maturation of pericytes and both the sprouting and survival of endothelial cells. These cellular deficits produced negative effects on vessel patency and leakiness, leading to retarded tumor progression. Taken together, these observations demonstrate the tight and extensive nature of interactions between the three vascular compartments. Disruption of any aspect of these interactions is detrimental to vessel development and function and has negative effects on tumor progression. This suggests the possible value of targeting all three microvascular components as a means of improving antiangiogenic therapy for tumors.