OVARIAN CARCINOMA--ROLE OF LAMININ AND ITS RECEPTORS

恶性卵巢癌多见于预后不良的患者 可能是由于他们的肿瘤固有的更具侵略性的行为 与良性或交界性囊腺瘤患者相比， 预后要好得多。原癌基因c-erb-B2已被证实 在卵巢原发上皮性肿瘤中扩增，以及一些研究 已经证明了基因扩增、癌基因表达、 并降低卵巢癌患者的存活率。组件 基底膜和细胞外基质是非常重要的。 各种细胞的生长、发育和分化的调节剂 类型。BM和ECM蛋白在表型调控中的作用 卵巢癌细胞的行为尚未得到彻底的研究 人们对此知之甚少。层粘连蛋白--主要的非胶原糖蛋白 已被证明能促进BM的黏附、铺展和 多种肿瘤细胞在体外的迁移。在预赛中 研究表明，我们观察到正常的人卵巢上皮细胞 粘附层粘连蛋白和较小的层粘连蛋白片段。有趣的是， 卵巢癌细胞系及其转染体的研究 C-erb基因表达增强的肿瘤细胞系 B2基因产物粘附层粘连蛋白的不同片段；提示 卵巢癌细胞可能改变了受体(S)对各种 层粘连蛋白的结构域。这些初步观察结果可能会提供一种 卵巢上皮细胞异常行为的解释 癌细胞，因为它们不再以正常的方式附着在 BM；相反，它们从BM释放，播种其他站点，发展成 腹水形成或侵入卵巢间质。假设是为了 被检测的是恶性卵巢的侵袭性行为越强 与正常卵巢上皮细胞相比，癌细胞是相关的 细胞对层粘连蛋白的反应改变，可能是由于 层粘连蛋白受体的变化。为了检验这一假设，它将是 已确定层粘连蛋白是否包含促进分化的序列 正常卵巢的粘连、扩散、迁移和/或侵袭 上皮性细胞与恶性卵巢上皮癌的比较 细胞。然后，将在以下行为之间建立关联 不同细胞对层粘连蛋白和层粘连蛋白序列的影响，以及c-erb-b的水平。 B2在细胞中的表达。另外，细胞表面的受体，特别是， 整合素亚单位，这些卵巢细胞用来与层粘连蛋白相互作用 并将确定层粘连蛋白的特定序列；这可能是 卵巢细胞的不同黏附和迁移 癌细胞。最后，将体外检测结果与 通过免疫组织化学定位层粘连蛋白和 良性正常卵巢上皮组织切片中的层粘连蛋白受体 浆液性囊腺瘤、交界性浆液性囊腺瘤和恶性 卵巢腺癌。将在两个数据之间建立关联 免疫组织化学染色模式、肿瘤的分期和 C-erb-B2水平。这些研究代表了一种 理解调控表型行为的分子机制 卵巢癌细胞的基因和潜在的辅助设计 用于治疗卵巢癌的生物药物。

Malignant ovarian carcinoma seen in patients who have a poor prognosis may be due to the inherently more aggressive behavior of their tumor cells compared to patients with benign or borderline cystadenomas, who have a much better prognosis. The proto-oncogene c-erb-B2 has been shown to be amplified in primary epithelial ovarian tumors, and some studies have shown a correlation between gene amplification, oncogene expression, and decreased survival in patients with ovarian cancer. Components of the basement membrane (BM) and extracellular matrix (ECM) are important modulators of growth, development, and differentiation for various cell types. The role of BM and ECM proteins in modulating the phenotypic behavior of ovarian carcinoma cells has not been thoroughly investigated and is poorly understood. Laminin, the major noncollagenous glycoprotein of the BM, has been shown to promote the adhesion, spreading, and migration of a variety of tumor cell types in vitro. In preliminary studies, we have observed that normal human ovarian epithelial cells adhere to laminin and to smaller fragments of laminin. Interestingly, ovarian carcinoma cell lines and transfectants of these ovarian carcinomas cell lines that contain an increased expression of the c-erb- B2 gene product adhere to different fragments of laminin; suggesting that ovarian carcinoma cells may have altered receptor(s) for the various domains of laminin. These preliminary observations may provide an explanation as to the abnormal behavior of the ovarian epithelial carcinoma cells, since they no longer adhere in a normal fashion to the BM; rather, they release from the BM, seed other sites, develop into an ascites form, or invade into the stroma of the ovary. The hypothesis to be tested is that the more aggressive behavior of the malignant ovarian carcinoma cells, compared to normal ovarian epithelial cells, is related to an altered cellular response towards laminin, perhaps due to alterations in laminin receptors. To test this hypothesis, it will be determined whether laminin contains sequences that promote differential adhesion, spreading, migration, and/or invasion of normal ovarian epithelial cells compared to malignant ovarian epithelial carcinoma cells. Correlations will then be made between the behavior of the various cells on laminin and laminin sequences, and the levels of c-erb- B2 in the cells. In addition, the cell surface receptors, in particular, integrin subunits, that these ovarian cells use to interact with laminin and specific sequences of laminin will be identified; this may be important for the differential adhesiveness and migration of ovarian carcinoma cells. Finally, the in vitro assays will be compared to what is observed in vivo, by immunohistochemically localizing laminin and laminin receptors in tissue sections of normal ovarian epithelium, benign serous cystadenomas, borderline serous cystadenomas, and malignant ovarian adenocarcinomas. Correlations will be made between the immunohistochemical staining patterns, the staging of the tumors, and the levels of c-erb-B2. These studies represent an approach towards understanding the molecular mechanisms modulating the phenotypic behavior of ovarian carcinoma cells and potentially aid in designing biopharmaceuticals for therapeutic use in ovarian cancer.