子宮体癌の予後因子に基づいた治療戦略 : 細胞形態と接着分子の側面から(<特集>第57回学術講演会シンポジウム: 子宮体癌の予後因子に基づいた治療戦略-その標準化を目指して-)

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Cell-cell adhesion participates in histogenesis and plays a critical role in the establishment and maintenance of cell polarity and cell society. Reduced cell-cell adhesiveness allows cancer cells to disobey the social order, resulting in destruction of the histological structure, the morphological hallmark of malignant tumors. In cancers in vivo, particularly the diffuse type, tumor cells are dissociated throughout the entire tumor mass, lose their cell polarity, and infiltrate the stroma in a scattered manner. Consistent with this concept, immunohistochemical studies have revealed that decreased E-cadherin expression was associated with tumor dedifferentiation and progression in endometrial carcinoma and other tumors. In the present study, we found hypermethylation in the promoter region of the E-cadherin gene and it was associated with tumor dedifferention and myometrial invasion in endometrial carcinoma. Tissue or cytological samples of endometrial cancer can be easily collected before surgery. Thus, it may be useful to analyze the existence of hypermathylation of the E-cadherin gene to predict the prognosis and select treatments. There are several lines of evidence suggesting that connexin expression is suppressed and/or aberrantly localized in pre-cancerous lesions in several organs and many, if not all, tumor-promoting agents have been shown to inhibit gap junctional intercellular communication (GJIC) of cultured cells as well as those in vivo, suggesting that the loss of GJIC enhances clonal dispersion, causing loss of the growth-suppression signals from the surrounding cells. For endometrial carcinogenesis, it may be concluded that the loss of GJIC caused by the suppressed expression and the aberrant localization of connexin support the clonal evolution of endometrial cancer cells originating in the hyperplasia cells. In the present study, GJIC of IKER1, which overexpresses ER-α, was markedly reduced in the estradiol-containing medium and the reduction was found to be inhibited by ICI182.780, a pure anti-estrogen substrate, as demonstrated by Lucifer-Yellow dye-transfer assay. Western blot analysis indicated that the expression of both Cx26 and Cx32 also decreased in E(+) and the reduction was inhibited by adding ICI182.780. These results supported the result of the dye-transfer assay. Thus, estrogen, which suppresses connexin expression of endometrial epithelium and causes cell proliferation, may act as a tumor-promoting agent for endometrium. Antitumor suicide gene therapy is one of the emerging strategies against cancer. It consists of the introduction into cancer cells of a gene capable of converting a nontoxic prodrug into a cytotoxic drug. Because this therapeutic gene cannot be easily introduced into the whole cell population of a tumor, the successful eradication of tumors depends on a phenomenon called the "bystander effect", by which the introduced gene can affect even cells in which it is not itself present. From a therapeutic point of view, it may be crucial to enhance this phenomenon through various means to achieve tumor eradication. One such suicide gene, the thymidine kinase gene from the herpes simplex virus, in combination with the prodrug ganciclovir, has been extensively and successfully used in some animal models exhibiting a strong bystander effect. Among the mechanisms involved in this phenomenon GJIC is directly involved in the transfer of the toxic metabolites of ganciclovir, which pass directly from herpes simplex virus thymidine kinase-expressing cells to surrounding cells that do not express it. Because GJIC appears to be a mediator of the bystander effect both in vitro and in vivo, here we review possible molecular strategies for enhancing the extent of tumor cell death by increasing the intratumoral GJIC capacity.
社団法人日本産科婦人科学会の論文
2005-11-01

子宮体癌の予後因子に基づいた治療戦略 : 細胞形態と接着分子の側面から(<特集>第57回学術講演会シンポジウム: 子宮体癌の予後因子に基づいた治療戦略-その標準化を目指して-)

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