Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target
Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target
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DOI：
10.1158/0008-5472.can-07-5167
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发表时间：
2008-04-01
期刊：
影响因子：
11.2
通讯作者：
Lengyel, Ernst
中科院分区：
文献类型：
--
作者：
Sawada, Kenjiro;Mitra, Anirban K.;Lengyel, Ernst
E-钙粘蛋白的丢失通常与卵巢癌转移有关。鉴于腹腔腹膜的粘附是卵巢癌扩散的第一步，我们推断下调E-钙粘蛋白会影响细胞基质粘附受体的表达。我们在此表明，抑制卵巢癌细胞中的E-钙粘蛋白导致α（5）-整合素蛋白表达和转录的上调。当E-cadherin被阻断时，RMUG-S卵巢癌细胞能够更有效地附着和侵入。反过来，这种更高的效率可以在体外和体内用α（5）β（1）-整联蛋白阻断抗体抑制。当E-钙粘蛋白沉默时，α 5-整联蛋白通过表皮生长因子受体/FAK/Erk 1-丝裂原活化蛋白激酶依赖性信号通路的激活而上调，而不是通过经典的E-钙粘蛋白/β-连环蛋白信号通路。在表达高水平α（5）-整联蛋白的SKOV-3 ip 1卵巢癌异种移植物中，与IgG治疗相比，用α（5）β（1）-整联蛋白抗体腹腔内治疗显著降低了肿瘤负荷、腹水和转移数目，并使存活率平均增加12天（P < 0.0005）。采用组织微阵列，通过免疫组织化学方法检测107例晚期卵巢癌中α（5）-整合素的表达，并对患者进行疾病特异性随访。107例组织中有10例（9%）有α（5）-整合素过度表达，39%有一定水平的α（5）-整合素表达。高α 5整合素水平患者的中位生存期为26个月，而低整合素表达患者的中位生存期为35个月（P < 0.05）。综上所述，我们已经确定α（5）-整合素上调作为一种分子机制，其中E-钙粘蛋白的损失促进肿瘤进展，提供了一个解释如何E-钙粘蛋白损失增加转移。针对这种整合素可能是一个有前途的治疗卵巢癌患者的子集。
E-cadherin loss is frequently associated with ovarian cancer metastasis. Given that adhesion to the abdominal peritoneum is the first step in ovarian cancer dissemination, we reasoned that down-regulation of E-cadherin would affect expression of cell matrix adhesion receptors. We show here that inhibition of E-cadherin in ovarian cancer cells causes up-regulation of alpha(5)-integrin protein expression and transcription. When E-cadherin was blocked, RMUG-S ovarian cancer cells were able to attach and invade more efficiently. This greater efficiency could, in turn, be inhibited both in vitro and in vivo with an alpha(5)beta(1)-integrin-blocking antibody. When E-cadherin is silenced, alpha 5-integrin is up-regulated through activation of an epidermal growth factor receptor/FAK/Erk1-mitogen-activated protein kinase-dependent signaling pathway and not through the canonical E-cadherin/beta-catenin signaling pathway. In SKOV-3ip1 ovarian cancer xenografts, which express high levels of alpha(5)-integrin, i.p. treatment with an alpha(5)beta(1)-integrin antibody significantly reduced tumor burden, ascites, and number of metastasis and increased survival by an average of 12 days when compared with IgG treatment (P < 0.0005). alpha(5)-Integrin expression was detected by immunohistochemistry in 107 advanced stage ovarian cancers using a tissue microarray annotated with disease-specific patient follow-up. Ten of 107 tissues (9%) had alpha(5)-integrin overexpression, and 39% had some level of alpha(5)-integrin expression. The median survival for patients with high alpha(5)-integrin levels was 26 months versus 35 months for those with low integrin expression (P < 0.05). Taken together, we have identified alpha(5)-integrin upregulation as a molecular mechanism by which E-cadherin loss promotes tumor progression, providing an explanation for how E-cadherin loss increases metastasis. Targeting this integrin could be a promising therapy for a subset of ovarian cancer patients.