TAKEICHI Masatoshi KYOTO University, Faculty of Science, Professor, 理学部, 教授 (00025454)
MATSUI Shigeo OSAKA University Medical School, Medical Staff, 医学部・附属病院, 医員
IWASAWA Takashi OSAKA University Medical School, Medical Staff, 医学部・附属病院, 医員
TAMURA Shigeyuki OSAKA University Medical School, Medical Staff, 医学部・附属病院, 医員
INOUE Masatoshi OSAKA University Medical School, Assistant Professor, 医学部, 助手 (80232560)
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,
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