title: An in vitro multistep carcinogenesis model for human cervical cancer.
abstract: Human papillomaviruses (HPV) are believed to be the primary causal agents for development of cervical cancer, and deregulated expression of two viral oncogenes E6 and E7 in basal cells, mostly by integration, is considered to be a critical event for disease progression. However, lines of evidence suggest that, besides expression of E6 and E7 genes, additional host genetic alterations are required for cancer development. To directly test this hypothesis, we first transduced HPV16 E6 and E7 with or without hTERT into several lines of normal human cervical keratinocytes (HCK) from independent donors and then searched for additional alterations required for carcinogenesis. Oncogenic Hras(G12V) (Hras) provided marked tumor forming ability in nude mice and ErbB2 or c-Myc (Myc) endowed weaker but significant tumor forming ability. Combined transduction of Myc and Hras to HCKs expressing E6 and E7 resulted in the creation of highly potent tumor-initiating cells. These results show that only one or two genetic changes occurring after deregulated expression of high-risk HPV oncogenes might be sufficient for development of cervical cancer.
authors.affiliation: Virology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Mako
authors.initials: M
authors.lastname: Narisawa-Saito
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yoshimatsu
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Ohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Yugawa
authors.forename: Nagayasu
authors.initials: N
authors.lastname: Egawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujita
authors.forename: Setsuo
authors.initials: S
authors.lastname: Hirohashi
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009368:Neoplasm Transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019098:Telomerase / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000209:etiology* / Q000473:pathology*
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D019098:Telomerase; C501009:HRAS protein, human