Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis
Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis
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DOI：
10.1158/0008-5472.can-04-2052
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发表时间：
2004-12-15
期刊：
影响因子：
11.2
通讯作者：
Olson, MF
中科院分区：
文献类型：
--
作者：
Croft, DR;Sahai, E;Olson, MF
肿瘤进展为侵袭性和转移性形式要求肿瘤细胞发生显著的形态变化，这一过程受Rho GTP酶调控。在人类癌症中通常观察到RhoA和RhoC以及Rho效应蛋白ROCK I和ROCK II的表达升高，并且往往与更具侵袭性和转移性的表型相关。为了研究ROCK如何促进实体瘤的进展，我们通过将激酶结构域与雌激素受体激素结合结构域融合，构建了一种条件性激活形式的ROCK II（ROCK:ER）。在免疫功能低下的裸鼠中作为肿瘤生长的表达ROCK:ER的结肠癌细胞围绕血管形成离散的细胞簇。然而，ROCKER激活导致肿瘤细胞向周围基质积极扩散，这表明ROCK信号增强足以促进实体瘤的侵袭。此外，ROCKER被激活的肿瘤血管化程度更高，这表明ROCK有助于肿瘤血管生成。ROCKER激活导致上皮形态和组织结构发生变化，这可能通过诱导诸如埃兹蛋白以及黏附连接和细胞外基质结合蛋白等蛋白质的重新分布，促进了体外的运动性。这些结果表明，在与RhoA、RhoC、ROCK I或ROCK II表达升高相关的肿瘤中，ROCK抑制剂将是有用的抗转移和抗血管生成化疗药物。
Progression of tumors to invasive and metastatic forms requires that tumor cells undergo dramatic morphologic changes, a process regulated by Rho GTPases. Elevated expression of RhoA and RhoC, as well as the Rho effector proteins ROCK I and ROCK II, are commonly observed in human cancers and are often associated with more invasive and metastatic phenotypes. To examine how ROCK contributes to the progression of solid tumors, we established a conditionally activated form of ROCK II by fusing the kinase domain to the estrogen receptor hormone-binding domain (ROCK:ER). ROCK: ER-expressing colon carcinoma cells grown as tumors in immunocompromised nude mice organized into discrete clusters surrounding blood vessels. However, ROCKER activation resulted in the aggressive dissemination of tumor cells into the surrounding stroma, indicating that increased ROCK signaling is sufficient to promote invasion from solid tumors. In addition, tumors in which ROCKER was activated were more highly vascularized, indicating that ROCK contributes to tumor angiogenesis. ROCKER activation resulted in changes to epithelial morphology and organization that facilitated motility in vitro, likely by inducing the redistribution of proteins such as ezrin, as well as adherens junction and extracellular matrix-binding proteins. These results suggest that ROCK inhibitors would be useful antimetastatic and antiangiogenic chemotherapeutic agents in tumors associated with elevated RhoA, RhoC, ROCK I, or ROCK II expression.