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The Mechanism of Human Esophageal Cancer lnvasion and Metastasis

人类食管癌侵袭和转移的机制

基本信息

批准号：
04454333
负责人：
SHIOZAKI Hitoshi
金额：
$ 4.48万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1994
项目状态：
已结题

项目摘要

We studied the role of an intercellular adhesion molecule, E-cadherin (ECD), in invasion and metastasis of human esophageal cancer. Using a cultured human esophageal cancer cell line (TE-2), ECD-positive (+) and ECD negative (-) cell lines were established. The ECD (+) cells demonstrated stronger intercellular adhesion, while ECD (-) cells showed more prominent migration. Addition of a human anti-ECD mAb (HECD-1) to cultures didnot alter the migration of ECD (-) cells, but it inhibited the adhesion of ECD (+) cells and promoted their migration. These results suggested that the migration and invasion of cancer cells may be enhanced by the reduction or loss of ECD.Using the same experimental system, we also assessed the effect of epidermal growth factor (EGF), which acts via the EGF receptor (EGFR), on the ECD-Ephi catenin intercellular adhesion system. 1) Aggregation assay : When the ECD (+) cellswere cultured on soft agar, they aggregated into balls. However, after the addition of EGF, … More the cells only formed small monolayred masses. When ECD (-) cells were cultured, they became fibroblast-like and addition of EGF had no effect. 2) alteration of ECD expression : ECD (+) cells showed strong ECD expression, confined to the cell membrane, but after the addition of EGF,ECD expression became widespread in the cells. 3)Invasion : When ECD (+) cells were cultured oncollagengel containing fibroblasts, they formed multilayredmasses. With the addition of EGF,they infiltrated into the gel. ECD (-) cells normally proliferated as monolayrs andinvaded into the gel, and these features were not changed bythe addition of EGF.4)Immunoblot analysis : ECD (+) cells were incubated with EGF and anti-ECD mAb (HECD-1) to produceimmunoprecipitation and the presence of phospho-tyrosine was invesigated. E catenin was converted into phosphotyrosine, suggesting that EGF-EGFR binding influencedthe cadoherin-catenin system and caused some abnormality of the intercellular adhesion mechanism. An immunohistochemicalinvestigation of human esophageal cancer tissue showed that lymph node metastasis occurred frequently with a poor prognosis in patients whose tumors exhibited reduced ECD orEphi-catenin expression.[Summary] Intercellular adhesion abnormalities, such as reduction of ECD orEphi catenin as wellas EGF-induced phospholyration of beta catenin, may contribute to invasion and metastasis of human esophageal cancer. Less

我们研究了细胞间粘附分子e -钙粘蛋白（ECD）在人食管癌侵袭转移中的作用。利用培养的人食管癌TE-2细胞系，建立ECD阳性（+）和ECD阴性（-）细胞系。ECD（+）细胞表现出更强的细胞间黏附，而ECD（-）细胞表现出更明显的迁移。在培养物中加入人抗ECD单抗（HECD-1）并不改变ECD（-）细胞的迁移，但抑制ECD（+）细胞的粘附并促进其迁移。这些结果表明，减少或丧失ECD可能会增强癌细胞的迁移和侵袭。使用相同的实验系统，我们还评估了表皮生长因子（EGF）对ECD-Ephi连环蛋白细胞间粘附系统的影响，EGF通过EGF受体（EGFR）起作用。1)聚集实验：ECD（+）细胞在软琼脂上培养，聚集成球。而加入EGF后，细胞只形成小的单层团块。当培养ECD（-）细胞时，它们变成成纤维细胞样，添加EGF对细胞无影响。2) ECD表达的改变：ECD（+）细胞表现出较强的ECD表达，局限于细胞膜，但加入EGF后，ECD在细胞中广泛表达。3)侵袭性：ECD（+）细胞与含成纤维细胞的胶原凝胶培养后，形成多层团块。随着EGF的加入，它们渗透到凝胶中。ECD（-）细胞通常呈单层增殖并侵入凝胶，这些特征没有因EGF的加入而改变。4)免疫印迹分析：ECD（+）细胞与EGF和抗ECD单抗（hed -1）孵育产生免疫沉淀，并研究磷酸酪氨酸的存在。E catenin转化为磷酸酪氨酸，提示EGF-EGFR结合影响了钙粘蛋白-catenin系统，导致细胞间粘附机制出现异常。一项对人食管癌组织的免疫组织化学研究表明，在ECD降低的肿瘤患者中，淋巴结转移经常发生，预后较差。【摘要】细胞间粘附异常，如ECD orEphi catenin的减少以及egf诱导的- catenin的磷酸化，可能与人食管癌的侵袭转移有关。少