Hendrix Mary J C, Seftor Elisabeth A, Kirschmann Dawn A, Quaranta Vito, Seftor Richard E B
Department of Anatomy and Cell Biology, The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242-1109, USA.
Ann N Y Acad Sci. 2003 May;995:151-61. doi: 10.1111/j.1749-6632.2003.tb03218.x.
A necessity for development and tumor progression is a blood supply formed by vasculogenic and/or angiogenic events, involving the cooperative interactions of cells with their microenvironment. Based on the recent characterization of vasculogenic mimicry by aggressive melanoma cells, particularly their ability to express VE (vascular endothelial)-cadherin, TIE-1, and EphA2, current studies have focused on the molecular signals deposited by these cells as they remodel their microenvironment. The experimental approach utilizes unique three-dimensional collagen matrices preconditioned by metastatic melanoma cells, which contain laminin 5 gamma2 chain-enriched tracks with promigratory cleavage fragments produced by cooperative interactions with specific matrix metalloproteinases (MMPs). The results demonstrate that the collagen matrices preconditioned by the metastatic cells induce poorly aggressive melanoma cells to express, for the first time, key angiogenic/vasculogenic/matrix-remodeling genes. Treatment of aggressive melanoma cells with an MMP inhibitor resulted in the inhibition of vasculogenic mimicry-associated genes in these tumor cells and abrogation of the inductive effects of the preconditioned matrix on poorly aggressive melanoma cells. These observations illustrate the remarkable influence of the microenvironment on the phenotype of melanoma cells and may provide new perspectives on tumor cell plasticity and unique treatment strategies.
肿瘤的发展和进展需要通过血管生成和/或血管形成事件形成血液供应，这涉及细胞与其微环境的协同相互作用。基于侵袭性黑色素瘤细胞对血管生成拟态的最新特征描述，特别是它们表达血管内皮（VE）-钙黏蛋白、TIE-1和EphA2的能力，目前的研究集中在这些细胞重塑其微环境时所沉积的分子信号上。实验方法利用由转移性黑色素瘤细胞预处理的独特三维胶原基质，其中含有富含层粘连蛋白5γ2链的轨迹以及与特定基质金属蛋白酶（MMP）协同相互作用产生的促迁移裂解片段。结果表明，由转移性细胞预处理的胶原基质首次诱导低侵袭性黑色素瘤细胞表达关键的血管生成/血管形成/基质重塑基因。用MMP抑制剂处理侵袭性黑色素瘤细胞导致这些肿瘤细胞中血管生成拟态相关基因的抑制，并消除了预处理基质对低侵袭性黑色素瘤细胞的诱导作用。这些观察结果说明了微环境对黑色素瘤细胞表型的显著影响，并可能为肿瘤细胞可塑性和独特的治疗策略提供新的视角。
