This project will investigate the genetic and epigenetic changes that occur during spontaneous transformation and tumor development in the WB-F344 liver stem-like epithelial cell line. Current data indicates that precursor cells are important targets during hepatocarcinogenesis, and transformed derivatives of WB-F344 cells produce a variety of phenotypes, including hepatocellular carcinomas, adenocarcinomas, hepatoblastomas, and undifferentiated spindle-cell tumors. The author hypothesizes that the genome becomes unstable during spontaneous malignant transformation, leading to aberrations in cellular DNA content and integrity. He predicts that the genomic instability that occurs during transformation causes aberrations in gene expression that allow the transformed cell to avoid cell cycle control and acquire autonomous replication potential, ultimately culminating in the formation of a tumor. The first goal of this proposal is to identify the mechanisms of genomic instability leading to fluctuations in DNA content in the WB-F344 cells during spontaneous transformation, and to identify the minimal genetic-epigenetic changes that are needed for malignant transformation. He will study the mechanisms of genomic instability in spontaneous transformants of WB-F344 by examining chromosomal ultrastructure during the transformation process by karyotype analysis and comparative genomic hybridization (CGH). The second goal is to evaluate the transforming potential of establishment of autocrine growth loops in normal, low-passage WB-F344 cells. This goal will be accomplished by characterizing tumor cell lines which have established autocrine loops, and by creating autocrine loops in otherwise normal, low-passage WB-F344 cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA059486-09
Application #
6350126
Study Section
Special Emphasis Panel (ZRG2-SSS-1 (04))
Program Officer
Okano, Paul
Project Start
1993-04-16
Project End
2003-01-31
Budget Start
2001-02-01
Budget End
2003-01-31
Support Year
9
Fiscal Year
2001
Total Cost
$238,361
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Pathology
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Kaufmann, W K; Behe, C I; Golubovskaya, V M et al. (2001) Aberrant cell cycle checkpoint function in transformed hepatocytes and WB-F344 hepatic epithelial stem-like cells. Carcinogenesis 22:1257-69
Golubovskaya, V M; Filatov, L V; Behe, C I et al. (1999) Telomere shortening, telomerase expression, and chromosome instability in rat hepatic epithelial stem-like cells. Mol Carcinog 24:209-17
Hooth, M J; Coleman, W B; Presnell, S C et al. (1998) Spontaneous neoplastic transformation of WB-F344 rat liver epithelial cells. Am J Pathol 153:1913-21
Presnell, S C; Hooth, M J; Borchert, K M et al. (1998) Establishment of a functional HGF/C-MET autocrine loop in spontaneous transformants of WB-F344 rat liver stem-like cells. Hepatology 28:1253-9
Hooth, M J; Vincent Jr, J L; Coleman, W B et al. (1998) Genomic fluidity is a necessary event preceding the acquisition of tumorigenicity during spontaneous neoplastic transformation of WB-F344 rat liver epithelial cells. Hepatology 28:78-85
Golubovskaya, V M; Presnell, S C; Hooth, M J et al. (1997) Expression of telomerase in normal and malignant rat hepatic epithelia. Oncogene 15:1233-40
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