Abstract

Tumor progression in diploid cells is a phenomenon that is characterized by a complex, usually slowly developing sequence of cellular reactions that is entrained by a rapid initiating event and is culminated by the development of a tumor (""""""""cancer""""""""). Initiation is necessary, but not sufficient to cause cells to acquire the ability to form tumors. Separating the appearance of malignant tumours from the initiating even are a series of apparently sequential phenotypic alterations in the population of cells at risk. Tumor progression has been viewed as a biological phenomenon essential to neoplastic transformation, during which initiated cells progressively develop phenotypic modifications that allow their selective multiplication and facilitate the emergence of successively more aberrant cells. Despite the general occurrence of this phenomenon of phenotypic alteration during carcinogenesis, the roles of the various phenotypically distinct populations of cells in emergence of tumorigenic cells is not clear. The goal of this project is to elucidate the role in tumor progression of cell populations expressing variant phenotypes. Sepcifically, we aim to determine whether preneoplastic phenotypes are obligatory or coincidental to tumor development, and, if obligatory, to determine whether various phenotypes represent linked sequential stages in the development of cancer. This project uses a line of cultured diploid hepatic epithelial cells from inbred rats that express selected hepatic function and produce carcinomas following transplantation into isogeneic hosts after in vitro treatment with MNNG. Tumor progression in cell populations in vitro is slow and is associated with the expression of several reproducible phenotypic changes which appear to be progressive and, possibly, sequential. Cultured cells can be mainpulated as single cells, and should allow the determination of whether any or all of the subpopulations that express altered phenotypes are required precursors of tumorigenic cells.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029323-05
Application #
3168649
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1981-02-01
Project End
1987-01-31
Budget Start
1985-02-01
Budget End
1986-01-31
Support Year
5
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

Gordon, Gavin J; Butz, Genelle M; Grisham, Joe W et al. (2002) Isolation, short-term culture, and transplantation of small hepatocyte-like progenitor cells from retrorsine-exposed rats. Transplantation 73:1236-43
Grisham, Joe W; Coleman, William B (2002) Molecular regulation of hepatocyte generation in adult animals. Am J Pathol 161:1107-10
Malouf, N N; Coleman, W B; Grisham, J W et al. (2001) Adult-derived stem cells from the liver become myocytes in the heart in vivo. Am J Pathol 158:1929-35
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
Gordon, G J; Coleman, W B; Hixson, D C et al. (2000) Liver regeneration in rats with retrorsine-induced hepatocellular injury proceeds through a novel cellular response. Am J Pathol 156:607-19
Gordon, G J; Coleman, W B; Grisham, J W (2000) Bax-mediated apoptosis in the livers of rats after partial hepatectomy in the retrorsine model of hepatocellular injury. Hepatology 32:312-20
Gordon, G J; Coleman, W B; Grisham, J W (2000) Induction of cytochrome P450 enzymes in the livers of rats treated with the pyrrolizidine alkaloid retrorsine. Exp Mol Pathol 69:17-26
Gordon, G J; Coleman, W B; Grisham, J W (2000) Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol 157:771-86
Coleman, W B; Ricketts, S L; Borchert, K M et al. (1999) Induction of rat WT1 gene expression correlates with human chromosome 11p11.2-p12-mediated suppression of tumorigenicity in rat liver epithelial tumor cell lines. Int J Oncol 14:957-63
McCullough, K D; Coleman, W B; Ricketts, S L et al. (1998) Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors. Proc Natl Acad Sci U S A 95:15333-8

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