# PROTOONCOGENES AND CELL LINEAGES IN LIVER CARCINOGENESIS

> **NIH NIH R01** · BROWN UNIVERSITY · 1993 · $194,112

## Abstract

Although liver carcinogenesis in rats has been extensively
investigated, the key molecular events which govern the various
stages of the process have not been defined.  Similarly, it has
been difficult to precisely trace the cell lineages of the tumors
which, in this system, emerge only after a very long induction
period.  The approach we have taken to study these problems centers
on the isolation and characterization of epithelial cell
populations which proliferate at the early stages of
hepatocarcinogenesis and contain most markers of liver neoplasia.
We now show that liver epithelial cells isolated from rats treated
with carcinogens for 2-6 weeks, placed in culture and transfected
with the EJ oncogene, can give rise to well differentiated
hepatocellular carcinomas when injected into nude mice.
Differentiation markers on cells of these tumors include the
reactivity with a panel of monoclonal antibodies and presence of
albumin mRNA.  In this application we propose to:  a) use this
novel system to analyze in detail the cell lineages of
hepatocellular carcinomas produced by EJ-transfected liver
epithelial cells and search for clonal lines which may contain
tumor stem cells; b) determine in vivo the developmental potential
and tumorigenicity of liver epithelial cells by transplanting cells
carrying appropriate marker genes into livers of syngeneic rats.

The liver epithelial cell system we have developed also permits an
analysis of the role of oncogenes and growth factors in the
development of hepatocellular carcinomas.  Although the EJ gene was
used to transform these cells, it is unlikely that this gene plays
a role in the development of most rat hepatocellular carcinomas in
vivo.  Instead, we propose to test the hypothesis that constitutive
expression of EGF receptor signals coupled with overexpression of
myc (or a member of the same gene family) may be sufficient to
transform liver epithelial cells.  Preliminary data indicate that
liver epithelial cell transformation is associated with the
blockage of an autocrine inhibitory circuit involving TGF-beta.
The proposed experiments should lead to the identification of
hepatocellular carcinoma cell lineages and provide new information
on the developmental potential and mechanisms of tumorigenesis of
liver epithelial cells.

## Key facts

- **NIH application ID:** 3172849
- **Project number:** 2R01CA035249-09
- **Recipient organization:** BROWN UNIVERSITY
- **SAM.gov UEI:** E3FDXZ6TBHW3
- **Principal Investigator:** NELSON FAUSTO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1993
- **Award amount:** $194,112
- **Award type:** 2
- **Project period:** 1983-07-01 → 1997-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3172849

## Citation

> US National Institutes of Health, RePORTER application 3172849, PROTOONCOGENES AND CELL LINEAGES IN LIVER CARCINOGENESIS (2R01CA035249-09). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3172849. Licensed CC0.

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