子宮頸癌の発生におけるIGF-Iレセプターの役割とIGF-Iレセプター分子標的治療の試み(1 子宮頸癌の発生と進展 : その制御を目指して)

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Type I Insulin-like Growth Factor (IGF-I) and its receptor (IGF-IR)play an important role in mitogenesis, differentiation, tranformation, and protection from apoptosis in various cancer cells. In cervical cancer patients, almost 90% are reported to be positive for human papillomavirus (HPV). It is well known that early proteins of HPV, E6 and E7 inactivate suppressor gene products pRB and p53, respectively. Transient transfection of E6 into SiHa cells up-regulated, and E2 into HeLa S3 cell down-regulated the expression levels of the IGF-IR. Stable transformant of SiHa cells with E6 showed marked decrease of anchorage-independent growth and tumorigenicity in vivo. In surgical specimens from CIN and cervical cancer patients, the expression level and activated IGR-IR gradually increased during the progression of cervical cancer. Down-regulation of the IGF-IR by stable expression of antisense mRNA resulted in reversal of the transformed phenotypes of both HPV positive and HPV negative cervical cancer cell lines, and completely abrogated tumorigenicity in vivo. These clones also showed increased chemosensitivity against taxol, due to the attenuated anti-apoptotic activity of the IGF-IR. Finally, administration of 486/STOP recombinant protein, a dominant negative of the IGF-IR with a bystander effect, retarded tumor growth of CaOV-3 cells in nude mice. The IGF-IR targeting for cervical cancer, whose IGF-IR expression level is exclusively regulated by E6 of HPV, can be a good candidate since up-regulation of the IGF-IR and its activation by its ligand play an important role in cervical cancer.
社団法人日本産科婦人科学会の論文
2002-08-01

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