Sanford-Burnham Medical Research Institute, Cancer Center, La Jolla, California.
Department of Histology, Microbiology, and Medical Biotechnologies, University of Padova, Padova, Italy.
Am J Pathol. 2012 Mar;180(3):1145-1158. doi: 10.1016/j.ajpath.2011.11.006. Epub 2011 Dec 23.
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.
为了研究血管基底膜在肿瘤血管形态发生和功能中的重要性，我们比较了野生型和胶原 VI 敲除小鼠大脑中肿瘤血管的发育、血管功能和进展。在没有胶原 VI 的 7 天肿瘤中，血管基底膜的宽度减少了两倍。尽管胶原 VI 的缺失并没有改变血管的丰度，但对周细胞或内皮细胞（或周细胞对内皮细胞的覆盖）数量的详细分析表明，在基底膜组装过程中胶原 VI 依赖性缺陷对周细胞成熟以及内皮细胞的发芽和存活都有负面影响。由于这些缺陷，血管通畅性降低了 25%，血管通透性增加了三倍，导致肿瘤缺氧增加了 10 倍，缺氧诱导因子-1α 的表达增加了 4 倍。在 12 天胶原 VI 敲除肿瘤中，血管内皮生长因子在整个肿瘤基质中表达增加，而在野生型肿瘤中血管内皮生长因子的表达主要呈血管模式。相应地，12 天胶原 VI 敲除肿瘤中的血管大小减小。总的来说，这些血管缺陷导致胶原 VI 敲除小鼠的肿瘤体积减少了两倍，证实了胶原 VI 依赖性基底膜组装是血管发育的一个关键方面。
