Fishman D A, Kearns A, Chilukuri K, Bafetti L M, O'Toole E A, Georgacopoulos J, Ravosa M J, Stack M S
Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Ill. 60611, USA.
Invasion Metastasis. 1998;18(1):15-26. doi: 10.1159/000024495.
Metastatic dissemination of epithelial ovarian carcinoma is thought to be mediated via tumor cell exfoliation into the peritoneal cavity, followed by adhesion to and invasion through the mesothelium which overlies the contents of the peritoneal cavity. In this study, we have utilized short-term primary cultures to analyze the effect of specific extracellular matrix proteins on properties of human ovarian epithelial carcinoma cells which contribute to the invasive phenotype. Analysis of cell:matrix adhesive profiles indicated that ovarian carcinoma cells adhere preferentially to type I collagen. Immunoprecipitation analyses demonstrated the presence of the collagen-binding alpha2beta1 integrin in biotin-labeled ovarian carcinoma cell membranes, and cellular adhesion was inhibited by blocking antibodies directed against the alpha2 and beta1 integrin subunits. The alpha2beta1-binding peptide Asp-Gly-Glu-Ala (DGEA) was also moderately effective at blocking adhesion to collagen relative to the control peptide Ala-Gly-Glu-Ala (AGEA). Analysis of cell motility on protein-coated colloidal gold coverslips demonstrated that ovarian carcinoma cells migrate preferentially on type I collagen coated surfaces. Type I collagen promoted migration in a concentration-dependent, saturable manner, with maximal migration observed at a collagen-coating concentration of 50 microg/ml. Migration on collagen was inhibited by antibodies directed against the alpha2 and beta1 integrin subunits and by DGEA peptide, providing evidence for the role of the alpha2beta1 integrin in ovarian carcinoma cell motility. Culturing ovarian carcinoma cells on type I collagen gels led to a significant increase in conversion of the matrix metalloproteinase 2 zymogen to the 66-kD form, suggesting that adhesion to collagen also influences matrix-degrading proteinases. These data suggest that alpha2beta1-integrin-mediated interaction of ovarian carcinoma cells with type I collagen, a protein prevalent both in the mesothelial extracellular matrix and in the peritoneal cavity of ovarian carcinoma patients, may function on multiple levels to promote metastatic dissemination of ovarian carcinoma cells.
上皮性卵巢癌的转移扩散被认为是通过肿瘤细胞脱落至腹腔，随后黏附并侵袭覆盖腹腔内容物的间皮来介导的。在本研究中，我们利用短期原代培养来分析特定细胞外基质蛋白对人卵巢上皮癌细胞有助于侵袭表型的特性的影响。细胞与基质黏附谱分析表明，卵巢癌细胞优先黏附于I型胶原。免疫沉淀分析显示，在生物素标记的卵巢癌细胞膜中存在胶原结合性α2β1整合素，并且针对α2和β1整合素亚基的阻断抗体可抑制细胞黏附。相对于对照肽丙氨酸-甘氨酸-谷氨酸-丙氨酸（AGEA），α2β1结合肽天冬氨酸-甘氨酸-谷氨酸-丙氨酸（DGEA）在阻断与胶原的黏附方面也有一定效果。在蛋白包被的胶体金盖玻片上对细胞运动性的分析表明，卵巢癌细胞优先在I型胶原包被的表面迁移。I型胶原以浓度依赖性、可饱和的方式促进迁移，在胶原包被浓度为50μg/ml时观察到最大迁移。针对α2和β1整合素亚基的抗体以及DGEA肽可抑制在胶原上的迁移，这为α2β1整合素在卵巢癌细胞运动性中的作用提供了证据。在I型胶原凝胶上培养卵巢癌细胞导致基质金属蛋白酶2酶原向66-kD形式的转化显著增加，这表明与胶原的黏附也会影响基质降解蛋白酶。这些数据表明，α2β1整合素介导的卵巢癌细胞与I型胶原的相互作用，I型胶原是间皮细胞外基质和卵巢癌患者腹腔中均普遍存在的一种蛋白，可能在多个层面发挥作用以促进卵巢癌细胞的转移扩散。
J Histochem Cytochem. 2017-11-22
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