(from applicant): One of the long standing unanswered questions in one of the most frequently studied models of carcinogenesis, chemical hepatocarcinogenesis, is what is the cell of origin of hepatocellular carcinomas (HCC)? The classic cellular pathway, championed by Emmanuel Farber, is that HCC develop from altered hepatocytes progressively through foci and preneoplastic nodules. However, studies on oval cells, which appear early during hepatocarcinogenesis, indicate that HCC may arise from """"""""bipolar"""""""" liver progenitor cells located within terminal ducts or from pluripotent progenitor cells located adjacent to the ducts. In addition, recent studies on female mice and rats receiving bone marrow transplants from male donors indicated two possible origins of liver stem cells: from bipolar progenitor cells in the terminal ducts or from periductal stem cells. It is further postulated that these periductal progenitor cells may arise from circulating bone marrow stem cells either by differentiation into liver cells or that bone marrow cells may fuse with liver cells.
In Specific Aim 1, the applicant proposes to develop a transgenic Fischer rat line expressing EGFP which can be used as a donor for bone marrow transplantation studies.
In Specific Aim 2, three models of carcinogenesis: a. Continuous DEN, which features foci of altered hepatocytes preceding HCC with little or no oval cells will be used to determine if HCC arise from hepatocytes; b. Solt-Farber model, which features prominent proliferation of ductal oval cells to determine if HCC arise from bipolar ductal precursor cells; c. Choline-deficiency-ethionine, a model which features periductular proliferation of oval cells will be used to determine if preneoplastic lesions or HCC arise from periportal oval cells. In each of these protocols, DDPIV- (canalicular enzyme) female rats will receive a bone marrow transplant from DDPIV+, EGFP+, male donors. The origin of the populations of cells responding by proliferation will be identified by the presence of donor or recipient markers, and the types of cells identified through labeling with both liver lineage and littoral cell markers, when appropriate.
In Specific Aim 3, the possibility of fusion of donor bone marrow stem cells with recipient liver cells will be tested and the possibility of fusion in etiology, progression or metastasis of HCC determined. Knowledge of the cellular origin of cancer is critical for understanding how cancer evolves and for developing prevention strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Etiology Study Section (CE)
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Yang, Shen K
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Ordway Research Institute, Inc.
United States
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Lanza, Denise Grant; Ma, Jun; Guest, Ian et al. (2012) Tumor-derived mesenchymal stem cells and orthotopic site increase the tumor initiation potential of putative mouse mammary cancer stem cells derived from MMTV-PyMT mice. Tumour Biol 33:1997-2005
Ma, Jun; Lanza, Denise Grant; Guest, Ian et al. (2012) Characterization of mammary cancer stem cells in the MMTV-PyMT mouse model. Tumour Biol 33:1983-96
Sell, S (2011) Infection, stem cells and cancer signals. Curr Pharm Biotechnol 12:182-8
Guest, Ian; Ilic, Zoran; Ma, Jun (2011) Preparation of epithelial and mesenchymal stem cells from murine mammary gland. Curr Protoc Toxicol Chapter 22:Unit22.3
Ilic, Zoran; Crawford, Dana; Vakharia, Dilip et al. (2010) Glutathione-S-transferase A3 knockout mice are sensitive to acute cytotoxic and genotoxic effects of aflatoxin B1. Toxicol Appl Pharmacol 242:241-6
Guest, Ian; Ilic, Zoran; Ma, Jun et al. (2010) Direct and indirect contribution of bone marrow-derived cells to cancer. Int J Cancer 126:2308-18
(2010) Corrigendum. Toxicol Appl Pharmacol 245:280
Guest, Ian; Ilic, Zoran; Sell, Stewart (2010) Age dependence of oval cell responses and bile duct carcinomas in male fischer 344 rats fed a cyclic choline-deficient, ethionine-supplemented diet. Hepatology 52:1750-7
Koch, Katherine S; Maeda, Shin; He, Guobin et al. (2009) Targeted deletion of hepatocyte Ikkbeta confers growth advantages. Biochem Biophys Res Commun 380:349-54
Sell, Stewart (2008) Alpha-fetoprotein, stem cells and cancer: how study of the production of alpha-fetoprotein during chemical hepatocarcinogenesis led to reaffirmation of the stem cell theory of cancer. Tumour Biol 29:161-80

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