Collagen VI Ablation Retards Brain Tumor Progression Due to Deficits in Assembly of the Vascular Basal Lamina

• DOI: 10.1016/j.ajpath.2011.11.006
• Publication Date: 2011-12-24T00:34:39Z
• Authors: Weon-Kyoo You; Paolo Bonaldo; William B. Stallcup
• Keywords: Vascular Endothelial Growth Factor A; 0301 basic medicine; Neovascularization, Pathologic; Brain Neoplasms; Endothelial Cells; Apoptosis; Collagen Type VI; Basement Membrane; Cell Hypoxia; Pathology and Forensic Medicine; 3. Good health; Mice, Inbred C57BL; Mice; Necrosis; 03 medical and health sciences; Disease Progression; Animals; Endothelium, Vascular; Hypoxia-Inducible Factor 1; Melanoma; Neoplasm Transplantation; Vascular Patency

To investigate the importance of the vascular basal lamina in tumor blood vessel morphogenesis and function, we compared vessel development, vessel function, and progression of B16F10 melanoma tumors in the brains of wild-type and collagen VI-null mice. In 7-day tumors in the absence of collagen VI, the width of the vascular basal lamina was reduced twofold. Although the ablation of collagen VI did not alter the abundance of blood vessels, a detailed analysis of the number of either pericytes or endothelial cells (or pericyte coverage of endothelial cells) showed that collagen VI-dependent defects during the assembly of the basal lamina have negative effects on both pericyte maturation and the sprouting and survival of endothelial cells. As a result of these deficits, vessel patency was reduced by 25%, and vessel leakiness was increased threefold, resulting in a 10-fold increase in tumor hypoxia along with a fourfold increase in hypoxia-inducible factor-1α expression. In 12-day collagen VI-null tumors, vascular endothelial growth factor expression was increased throughout the tumor stroma, in contrast to the predominantly vascular pattern of vascular endothelial growth factor expression in wild-type tumors. Vessel size was correspondingly reduced in 12-day collagen VI-null tumors. Overall, these vascular deficits produced a twofold decrease in tumor volume in collagen VI-null mice, confirming that collagen VI-dependent basal lamina assembly is a critical aspect of vessel development.