Document Detail


Creation of tumorigenic human endometrial epithelial cells with intact chromosomes by introducing defined genetic elements.
MedLine Citation:
PMID:  16636665     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Several genetic mutations have been identified in human endometrial cancers, but the specific combinations of mutations required to form endometrial cancer cells remain unknown. In the present study, we established an in vitro model of endometrial carcinogenesis, in which defined genetic elements were introduced into endometrial epithelial cells to create transformed endometrial cells at different stages. Introduction of the human papillomavirus type 16 E6/E7 gene and the human telomerase reverse transcriptase (hTERT) gene into human primary endometrial epithelial cells was sufficient to generate immortalized cells. Introduction of hTERT in early passages stabilized telomeres and created immortalized cells with normal karyotype, whereas introduction of hTERT in later passages generated immortalized cells but with widespread chromosome abnormalities. However, neither of those two immortalized cell lines exhibited tumorigenic phenotypes. Tumorigenic endometrial epithelial cells with invasive capacity were created by introducing a mutant K-ras allele into immortalized cells, keeping their chromosomes intact. Inhibiting the PTEN gene and activating Akt pathways did not create tumorigenic phenotypes, although the latter conferred anchorage-independent growth capacity. These findings suggest that neoplastic transformation of human endometrial cells can occur in the absence of widespread chromosomal abnormality, and that the combination of Rb inactivation, telomerase activation and altered K-ras signaling is sufficient for in vitro neoplastic transformation. The present experimental model can help clarify the genetic requirements for endometrial carcinogenesis, and it is useful for testing and developing specific inhibitors of specific oncogenic pathways.
Authors:
Y Mizumoto; S Kyo; S Ohno; M Hashimoto; M Nakamura; Y Maida; J Sakaguchi; M Takakura; M Inoue; T Kiyono
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-04-24
Journal Detail:
Title:  Oncogene     Volume:  25     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-09-14     Completed Date:  2006-10-18     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  5673-82     Citation Subset:  IM    
Affiliation:
Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Cell Transformation, Neoplastic
Chromosomes, Human*
DNA Primers
DNA-Binding Proteins / genetics
Endometrial Neoplasms / genetics*,  pathology
Epithelial Cells
Female
Genes, ras
Humans
Mice
Mice, Nude
Microsatellite Repeats / genetics
Mutation
PTEN Phosphohydrolase / genetics
Telomerase / genetics
Chemical
Reg. No./Substance:
0/DNA Primers; 0/DNA-Binding Proteins; EC 2.7.7.49/Telomerase; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.67/PTEN Phosphohydrolase

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