TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression.
TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression.
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DOI：
10.1371/journal.pone.0077366
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Gong Y;Scott E;Lu R;Xu Y;Oh WK;Yu Q
晚期前列腺癌和结肠癌的治疗选择有限，迫切需要开发更有效和更有针对性的新疗法，这首先要从识别和验证新的治疗靶点开始。最近的临床研究表明，肿瘤患者血浆中组织抑制物基质金属蛋白酶-1(TIMP-1)水平升高，且TIMP-1水平升高与临床预后不良有关。然而，目前尚不清楚TIMP-1是仅仅作为癌症进展的生物标志物，还是具有促进癌症进展的功能，并可以作为癌症治疗的靶点，这是本研究的主要目的。在这里，我们发现人类前列腺癌和结肠癌的间质中TIMP-1的表达水平高于正常对照，并且TIMP-1的表达增加促进了这两种癌症的体内生长。我们首次证明了TIMP-1的表达增加刺激了前列腺癌和结肠癌组织中癌症相关成纤维细胞(CAF)的聚集，并且TIMP-1在体外促进了前列腺癌CAF的增殖和迁移，并促进了这些CAF细胞中ERK1/2的激活。我们的结果建立了TIMP-1在癌症进展和CAF积累方面的新的促进作用，这反过来提供了一个有利于肿瘤的微环境。综上所述，这些结果确立了TIMP-1作为癌症治疗新靶点的潜力以及TIMP-1促肿瘤活性的机制。
Treatment options for late stage prostate and colon cancer are limited and there is an urgent need to develop more effective and targeted novel therapies, which starts with identification and validation of novel therapeutic targets. Recent clinical studies have demonstrated that tissue inhibitor matrix metalloproteinase-1 (TIMP-1) levels are elevated in cancer patient plasma and elevated TIMP-1 levels are associated with worse clinical outcomes. However, it is unknown whether TIMP-1 serves merely as a biomarker of cancer progression or has a functional role in promoting cancer progression and can serve as a cancer therapeutic target, which is the main objective of this study. Here, we show that stroma of human prostate and colon cancer express higher levels of TIMP-1 compared to their normal counterparts and increased expression of TIMP-1 promotes in vivo growth of both cancer types. We demonstrate for the first time that increased TIMP-1 expression stimulates accumulation of cancer associated fibroblasts (CAFs) within prostate and colon cancer tissues and that TIMP-1 enhances prostate CAF proliferation and migration in vitro and promotes ERK1/2 kinase activation in these CAF cells. Our results establish the novel promotive effects of TIMP-1 on cancer progression and on accumulation of CAFs that in turn provides a pro-tumor microenvironment. Together, these results establish the potential of TIMP-1 as a novel target for cancer therapy and the mechanism underlying the pro-tumor activity of TIMP-1.
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影响因子：
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