Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion.
Carcinomas contain a matrix metalloproteinase-resistant isoform of type I collagen exerting selective support to invasion.
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DOI：
10.1158/0008-5472.can-09-4057
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发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Leikin S
中科院分区：
文献类型：
--
作者：
Makareeva E;Han S;Vera JC;Sackett DL;Holmbeck K;Phillips CL;Visse R;Nagase H;Leikin S
胶原纤维以两种相反的方式影响转移，通过支持侵袭细胞，但也产生侵袭屏障。我们假设这些功能可能是由I型胶原的不同亚型完成的。据报道，癌症含有α1（I）3同源三聚体，一种通常不存在于健康组织中的I型胶原亚型，但同源三聚体在癌症病理生理学中的作用尚不清楚。在这项研究中，我们发现这些同源三聚体对所有的胶原溶解性基质金属蛋白酶（MMPs）都有抗性。MMP被癌细胞和癌症相关成纤维细胞大量产生和利用，用于在肿瘤侵袭的前沿降解基质胶原。MMP抗性同源三聚体由测试的所有侵袭性癌细胞系在培养物和肿瘤异种移植物中产生，但它们不由癌症相关的成纤维细胞产生，从而包含肿瘤胶原的专门级分。我们观察到同源三聚体纤维对细胞周围降解具有抗性，甚至在用促炎细胞因子刺激细胞后也是如此。此外，我们证实了同源三聚体与正常（异源三聚体）I型胶原纤维表面上浸润性癌细胞的增殖和迁移增强。总之，我们的研究结果表明，侵袭性癌细胞可以利用同源三聚体来构建MMP抗性的侵袭路径，支持局部增殖和细胞的定向迁移，同时周围的正常基质胶原蛋白被切割。由于同源三聚体普遍由癌细胞分泌并沉积为不溶性的MMP抗性纤维，因此它们为癌症诊断和治疗提供了一个有吸引力的靶标。
Collagen fibers affect metastasis in two opposing ways, by supporting invasive cells but also generating a barrier to invasion. We hypothesized that these functions might be performed by different isoforms of type I collagen. Carcinomas are reported to contain α1(I)3 homotrimers, a type I collagen isoform normally not present in healthy tissues, but the role of the homotrimers in cancer pathophysiology is unclear. In this study, we found that these homotrimers were resistant to all collagenolytic matrix metalloproteinases (MMPs). MMPs are massively produced and utilized by cancer cells and cancer-associated fibroblasts for degrading stromal collagen at the leading edge of tumor invasion. The MMP-resistant homotrimers were produced by all invasive cancer cell lines tested, both in culture and in tumor xenografts, but they were not produced by cancer-associated fibroblasts, thereby comprising a specialized fraction of tumor collagen. We observed the homotrimer fibers to be resistant to pericellular degradation, even upon stimulation of the cells with pro-inflammatory cytokines. Further, we confirmed an enhanced proliferation and migration of invasive cancer cells on the surface of homotrimeric vs. normal (heterotrimeric) type I collagen fibers. In summary, our findings suggest that invasive cancer cells may utilize homotrimers for building MMP-resistant invasion paths, supporting local proliferation and directed migration of the cells while surrounding normal stromal collagen is cleaved. Because the homotrimers are universally secreted by cancer cells and deposited as insoluble, MMP-resistant fibers, they offer an appealing target for cancer diagnostics and therapy.