Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix
Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix
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DOI：
10.1016/s0092-8674(03)00513-0
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发表时间：
2003-07-11
期刊：
影响因子：
64.5
通讯作者：
Weiss, SJ
中科院分区：
文献类型：
--
作者：
Hotary, KB;Allen, ED;Weiss, SJ
癌细胞能够在富含I型胶原蛋白的三维（3D）细胞外基质（ECM）环境中加速增殖。肿瘤细胞用于规避内源性抗生长信号的机制尚未明确界定。我们发现基质金属蛋白酶MT1 - MMP在体外和体内赋予肿瘤细胞独特的3D生长优势。MT1 - MMP所赋予的增殖优势需要细胞外基质的细胞周蛋白水解，因为当肿瘤细胞悬浮在抗蛋白酶的胶原蛋白3D凝胶中时，增殖被完全抑制。在没有蛋白水解的情况下，嵌入生理相关细胞外基质中的肿瘤细胞被困在紧凑的球形结构中，无法进行3D生长所需的细胞形状改变或细胞骨架重组。这些观察结果表明MT1 - MMP是一种肿瘤衍生的生长因子，它通过控制三维细胞外基质环境中的细胞几何形状来调节增殖。
Cancer cells are able to proliferate at accelerated rates within the confines of a three-dimensional (313) extracellular matrix (ECM) that is rich in type I collagen. The mechanisms used by tumor cells to circumvent endogenous antigrowth signals have yet to be clearly defined. We find that the matrix metalloproteinase, MT1-MMP, confers tumor cells with a distinct 3D growth advantage in vitro and in vivo. The replicative advantage conferred by MT1-MMP requires pericellular proteolysis of the ECM, as proliferation is fully suppressed when tumor cells are suspended in 3D gels of protease-resistant collagen. In the absence of proteolysis, tumor cells embedded in physiologically relevant ECM matrices are trapped in a compact, spherical configuration and unable to undergo changes in cell shape or cytoskeletal reorganization required for 3D growth. These observations identify MT1-MMP as a tumor-derived growth factor that regulates proliferation by controlling cell geometry within the confines of the 3D ECM.