QUANTIFYING GENE EFFECTS ON HEPATIC CANCER IN VIVO

University Of Wisconsin-Madison, Madison WI

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Abstract

The overall goal of this proposed research is to assign a role in hepatocarcinogenesis of each of several[unreadable] genetic changes commonly identified in human and/or mouse liver tumors. To accomplish this objective, a[unreadable] newly developed, novel in vivo assay system is employed, the comparative hepatocyte growth assay. As[unreadable] starting material, this assay uses rodents that have been genetically modified to reflect activation of[unreadable] proposed carcinogenic pathways. Hepatocytes are isolated from these animals, and then transplanted into[unreadable] liver of specially designed recipient mice with liver disease that support transient replication of donor[unreadable] hepatocytes: Evaluation of the subsequent clonal growth of donor cells in the new host environment allows[unreadable] quantification of the influence of single or combined genetic modifications on (1) the rate at which[unreadable] hepatocytes proliferate under growth stimulatory conditions; (2) the capacity for sustained hepatocyte growth[unreadable] in a quiescent liver environment; and (3) the risk for hepatocyte progression to malignant transformation.[unreadable] Each measure reflects an important characteristic of neoplastic cells. The quantitative nature of the data.[unreadable] provides a more refined understanding of the specific contribution of each genetic change, alone and in[unreadable] combination with others, to hepatocarcinogenesis. The final objective is to use this system as a tool for[unreadable] cancer gene discovery, by correlating changes in patterns of gene expression with the changes in[unreadable] hepatocyte clonal growth that will be identified. The proposal has the following specific aims. Aim 1: Define[unreadable] the effects of specified combinations of gene changes on mouse hepatocarcinogenesis. Aim 2: Quantify[unreadable] effects of defined gene changes on hepatocyte growth and transformation frequency in vivo. Aim 3: Identify[unreadable] growth characteristics and changes in the pattern of gene expression of transformed hepatocytes in vivo.[unreadable] Successful completion of these experiments will (1) define specific interactions between several highly[unreadable] relevant genetic changes (synergistic or additive complementation, or no complementation) during hepatic[unreadable] carcinogenesis; (2) provide a systematic and comparative evaluation of the influence of genetic and[unreadable] environmental alterations, selected for their relevance to liver cancer, on hepatocyte growth potential; and (3)[unreadable] will identify gene sets that cooperate with oncogenes during tumor progression.