Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen.
Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen.
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DOI：
10.1158/0008-5472.can-15-0964
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发表时间：
2015-10-01
期刊：
影响因子：
11.2
通讯作者：
Palumbo JS
中科院分区：
文献类型：
--
作者：
Adams GN;Rosenfeldt L;Frederick M;Miller W;Waltz D;Kombrinck K;McElhinney KE;Flick MJ;Monia BP;Revenko AS;Palumbo JS
凝血酶介导的蛋白分解是转移的主要决定因素，但对原发肿瘤的生长并不是普遍重要的。在这里，我们报告结直肠腺癌是一个重要的例外，凝血酶介导的功能支持原发肿瘤的生长和转移。与多发性非胃肠道肿瘤的研究相比，我们发现小鼠和人结肠癌细胞形成的原发肿瘤的生长通过基因或药物减少循环凝血酶原而减少。凝血酶原表达降低与核分裂指数降低和周围组织侵袭有关。机制研究表明，凝血酶驱动的结肠腺癌的生长依赖于至少两个凝血酶介导的蛋白分解靶点，即基质细胞表达的蛋白酶激活受体-1(PAR-1)和细胞外基质蛋白纤维蛋白原。在PAR-1缺陷的小鼠中，结肠腺癌的生长减少，这意味着基质细胞相关的PAR-1是肿瘤生长的一个重要的凝血酶靶点。此外，纤维蛋白原缺陷小鼠的肿瘤生长显著受阻，这首次直接证明了纤维蛋白原在恶性肿瘤生长中的关键功能作用。来自纤维蛋白原缺陷小鼠的肿瘤细胞增殖指数相对降低，肿瘤坏死增加，肿瘤血管密度降低。总而言之，我们的发现确立了凝血酶及其靶标PAR-1和纤维蛋白原在结肠腺癌发病机制中的功能作用，支持肿瘤生长以及局部侵袭和转移。
Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1–deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.