Research Interests
Expression of a neoplastic phenotype requires both the acquisition of critical changes in genomic DNA, which results in altered patterns of gene expression, and the escape of the altered cell from the suppressive effects of the tissue microenvironment which regulate cellular proliferation and impose the differentiated phenotype. Our recent research has demonstrated that the microenvironment of normal adult liver can impose differentiation on neoplastic liver epithelial cells that rapidly form tumors at subcutaneous or intraperitoneal sites. The capacity of normal liver to suppress tumorigenicity decreases with age; transformed cells which differentiate if transplanted into the liver of young animals form tumors if transplanted into the livers of elderly animals. The major emphasis of current research is focused on identification of factors in the liver of young animals that are involved in the suppression of the tumorigenic genotype and genes whose expression is correlated with susceptibility/insensitivity to suppression. A similar research effort is focused on the role of age and prostatic microenvironment on the expression of tumorigenicity by transformed prostatic stem cell lines transplanted into the prostate. The prostate is an interesting model to study the correlation of age and neoplasia because the tissue microenvironment of the prostate is better characterized than that of liver and the majority of human prostate cancer is characterized by indolent disease contained within the prostate. Correlated studies are evaluating the influence of the prostate microenvironment on prostate stem cells as the source of prostatic adenocarcinoma and on their pluripotent potential.

Genomic instability, the loss of control over the exact segregation of DNA to the daughter cells, is a hallmark of neoplastic cells. However, it is not known if genomic instability precedes the acquisition of neoplastic potential, and accelerates the develop of tumorigenicity, or if genomic instability is initiated after the cell has become tumorigenic. Our recent studies have demonstrated that genomic instability appears to precede the acquisition of a neoplastic phenotype and suggest that cells may go through cycles of gain and lose of DNA before they become tumorigenic. Additionally, multiple cell lines reverted to a pseudo-diploid cellular DNA content before they became tumorigenic, which suggests a mechanism for controlling the amount of DNA that can be replicated and sequestered within a nucleus. These studies are aimed at identifying genes, particularly genes associated with cell cycle restriction points or checkpoints, and areas of the genome that are correlated with the appearance of genomic instability and acquisition/suppression of tumorigenic potential. In addition, digital imaging is being employed to characterize the distribution of chromatin, nuclear structure and nuclear division in neoplastic and normal cells.

Publications
McCullough, K.D., Coleman, W.B., Smith, G.J., and Grisham, J.W. (1997) Age-dependent induction of hepatic tumor regression by the tissue microenvironment after transplantation of neoplastically transformed rat liver epithelial cells into the liver. Cancer Res. 57: 1807-1813.

Presnell, S.C., Gregory, C.W., Mohler, J.L., and Smith, G.J. (1998) Isolation and Characterization of a propagable cell line (HUNC) from an androgen-sensitive Dunning R3327H rat prostatic adenocarcinoma. Carcinogenesis. 19: 585-590.

Presnell, S.C., Hooth, M.J., Borchert, K.M., Coleman, W.B., Grisham, J.W., and Smith, G.J. (1998) Establishment of a functional hepatocyte growth factor/c-met autocrine loop in spontaneous transformants of WB-F344 rat liver epithelial stem-like cells. Hepatology. 28: 1253-1259.

Hooth, M.J., Vincent, J.L., Coleman, W.B., Presnell, S.C., Grisham, J.W. and Smith, G.J. 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.

McCullough, K.D., Coleman, W.B., Smith, G.J. and Grisham, J.W. (1998) Plasticity of the neoplastic phenotype in vivo is regulated by epigenetic factors. Proc. Nat. Acad. Sci. (USA). 95: 15333-15338.

E-mail: cellsort@med.unc.edu
Telephone: (919) 966-2699
FAX: (919)966-5046
Address: 414 Brinkhous-Bullitt Bldg., CB# 7525 Chapel Hill, NC

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