子宮頚部扁平上皮・頚管腺上皮の分化調節機序の解析に基づく頚癌初期発生過程の研究 (<シンポジウム>子宮頚部の初期癌ならびにその関連病変)

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Recently cervical cancer is defined as a sexually-transmitted disease, and human papillomavirus (HPV) has been focused as one of its etiologic agents. It is known that cervical cancer is extraordinarily rare in non-human mammals that have the estrous cycle. In contrast, cervical cancer is frequent in human beings which have lost the estrous cycle, and subsequently evolved a sexual behavior irrespective of the menstrual phase. Therefore, upon the hypothesis that the estrous cycle is a period protected from a sexually transmitted disease, we studied the status of local defence mechanism and growth/differentiation of normal cervical epithelium during the menstrual cycle and pregnancy. Then, the influence of HPV-infection on the growth and differentiation of cervical epithelium was analyzed. As a local immune system of the cervix, both IgA and IgG are secreted in the cervical mucus, and the levels in the follicular phase were significantly higher than those during the luteal phase and pregnancy. An existence of local defence mechanism in the follicular phase is suggested. Analysis of a cell proliferation antigen Ki-67 in normal cervix revealed that parabasal cells enter the cell cycle more frequently in the luteal phase than in the follicular phase. Basal and reserve cells are usually resting, but a few cells enter the cell cycle during the luteal phase and during pregnancy. Since cycling cells are more susceptible to viral infection, the basal and/or reserve cells during the luteal phase and pregnancy are suggested to be under the risk for HPV infection. As factors regulating growth and differentiation of cervical squamous epithelium, immunohistochemical expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor (EGFR), c-erbB-2 protein, adult T-cell leukemia-derived factor (ADF), and HPV DNA was examined. In normal cervix, basal cells were usually ER-positive and PR-negative. Parabasal cells were ER-positive and PR-negative in the follicular phase, while they were ER-negative and PR-positive during the luteal phase and pregnancy. Considering the results of Ki-67 expression, the ER-negative and PR-positive status is possibly related to the proliferation of the cervical squamous epithelium. In cervical condylomas, basal cells infected by HPV6/11 were ER-positive, but HPV16/18-infected cells were ER-negative. Neoplastic cells of CINs and invasive squamous carcinomas containing HPV DNA 16/18 were ER-negative, while those containing HPV DNA 31/33/35 were weakly ER-positive. PR was positive in 2 of 2 condylomas, 18 of 26 CINs, and 13 of 22 invasive carcinomas. Consequently, neoplastic squamous cells infected by HPV, especially types 16/18, show down-expression of ER and up-expression of PR which are the characteristics of the receptor status of cervical squamous proliferation. In addition, experiment of HPV16 DNA transfection into the ER-positive mammary cancer cell line (ZR-75-1) resulted in its down-expression of ER. This suggests that HPV DNA may directly affect the expression of ER. In normal cervix, basal or reserve cells were EGFR-positive and c-erbB-2 protein-negative, while intermediate cells were EGFR-negative and c-erbB-2 protein-positive. Consequently, c-erbB-2 protein expression may be closely associated with the differentiation of cervical epithelium. Condylomas and CINs were strongly positive for EGFR and almost negative for c-erbB-2 protein. Therefore, HPV-infection may also affect the differentiation of cervical squamous cells. ADF, a polypeptide derived from a HTLV-1 transformed cell line, is currently considered as a human thioredoxin which participates in various cell functions. Normal cervical epithelium was ADF-negative. In condylomas and CINs, ADF was positive in the cells of intermediate and superficial layers. In addition, HPV DNA was localized in almost the same cells that were ADF-positive. Such topological localization of ADF and HPV DNA suggests that ADF-expression is
社団法人日本産科婦人科学会の論文
1990-08-01

子宮頚部扁平上皮・頚管腺上皮の分化調節機序の解析に基づく頚癌初期発生過程の研究 (<シンポジウム>子宮頚部の初期癌ならびにその関連病変)

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