Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells
Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells
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DOI：
10.1158/0008-5472.can-06-2808
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发表时间：
2007-03-01
期刊：
影响因子：
11.2
通讯作者：
Stack, M. Sharon
中科院分区：
文献类型：
--
作者：
Symowicz, Jaime;Adley, Brian P.;Stack, M. Sharon
细胞-细胞粘附、细胞-基质粘附和蛋白水解活性的可逆调节在转移过程中肿瘤性卵巢上皮的重塑中起着关键作用，这涉及腹腔注射中的钙粘蛋白、整合素和蛋白酶。上皮性卵巢癌（EOC）的转移性播散。异常的上皮分化是卵巢癌发生的早期事件。因此，与大多数随着进展而失去E-钙粘蛋白表达的癌症相反，E-钙粘蛋白在原发性EOC中丰富。转移性上皮细胞参与整合素介导的与间皮下间质胶原的粘附，并表达促进胶原侵袭的基质金属蛋白酶（MMP），从而将继发性病变锚定在间皮下基质中。由于金属蛋白酶也与 E-钙粘蛋白胞外域脱落有关，因此当前的研究旨在模拟基质诱导的整合素聚类对蛋白酶催化的 E-钙粘蛋白胞外域脱落的影响。胶原蛋白结合整合素的聚集诱导 80 kDa E-钙粘蛋白胞外域 [可溶性 E-钙粘蛋白 (sE-cad)] 以 MMP 和 Src 激酶依赖性方式脱落，并且 sE-cad 在卵巢癌患者的腹水中普遍存在。 MMP-9 的表达通过整合素聚集而升高，整合素介导的胞外域脱落被 MMP-9 功能阻断抗体抑制，并且细胞与外源 MMP-9 一起孵育可催化 E-钙粘蛋白胞外域脱落。与 sE-cad 释放到循环中的其他肿瘤相比，EOC 肿瘤与高浓度的富含 sE-cad 的腹水保持直接接触，并且将 EOC 细胞与生理相关浓度的重组 sE-cad 一起孵育，破坏粘附连接。这些数据支持通过细胞-基质接触引发的 MMP-9 诱导对 E-钙粘蛋白功能进行翻译后修饰的新机制，并提出了一种促进 EOC 转移扩散的机制。
Reversible modulation of cell-cell adhesion, cell-matrix adhesion, and proteolytic activity plays a critical role in remodeling of the neoplastic ovarian epithelium during metastasis, implicating cadherins, integrins, and proteinases in i.p. metastatic dissemination of epithelial ovarian carcinoma (EOC). Aberrant epithelial differentiation is an early event in ovarian carcinogenesis; thus, in contrast to most carcinomas that lose E-cadherin expression with progression, E-cadherin is abundant in primary EOC. Metastasizing EOCs engage in integrin-mediated adhesion to submesothelial interstitial collagens and express matrix metalloproteinases (MMP) that facilitate collagen invasion, thereby anchoring secondary lesions in the submesothelial matrix. As metalloproteinases have also been implicated in E-cadherin ectodomain shedding, the current study was undertaken to model the effects of matrix-induced integrin clustering on proteinase-catalyzed E-cadherin ecto-domain shedding. Aggregation of collagen-binding integrins induced shedding of an 80-kDa E-cadherin ectodomain [soluble E-cadherin (sE-cad)] in a MMP- and Src kinase-dependent manner, and sE-cad was prevalent in ascites from ovarian cancer patients. Expression of MMP-9 was elevate by integrin aggregation, integrin-mediated ectodomain shedding was inhibited by a MMP-9 function blocking antibody, and incubation of cells with exogenous MMP-9 catalyzed E-cadherin ectodomain shedding. In contrast to other tumors wherein sE-cad is released into the circulation, EOC tumors maintain direct contact with sE-cad-rich ascites at high concentration, and incubation of EOC cells with physiologically relevant concentrations of recombinant sE-cad disrupted adherens junctions. These data support a novel mechanism for posttranslational modification of E-cadherin function via MMP-9 induction initiated by cell-matrix contact and suggest a mechanism for promotion of EOC metastatic dissemination.