HGF AND TUMOR PROMOTION--AN HGF-TRANSGENIC MOUSE MODEL

Cell proliferation and growth is believed to be necessary for promotion
of tumors and carcinogenesis. In the case of liver, hepatocyte
replication and growth is an essential process during the long period of
progression to cancer. Recently, a potent hepatomitogen (Hepatocyte
Growth Factor, HGF) has emerged as one of the most likely hepatotrophic
agents responsible for maintenance of hepatocyte growth and
proliferation. Despite significant progress in characterizing the
biochemical and biological properties of HGF, the precise physiological
role of this potent epithelial mitogen is unknown in normal and abnormal
cell growth. We have generated several lines of transgenic mice
harboring a human HGF cDNA under the transcriptional control of mouse
Metallothionein 1 promoter. These transgenic animals can provide a
suitable model system to further explore the effects of directed high
expression of HGF in liver tumor promotion and carcinogenesis induced by
different xenobiotics. Utilizing these animals we would like to address
the following questions: A) What are the effects of long term and
continuous expression of HGF in MT1-HGF transgenic mice in the liver and
other tissues? B) Does the chronic overexpression of HGF in MT1-HGF
transgenic mice in conjunction with different liver tumor promoters and
carcinogens lead to enhanced appearance of pre-neoplastic and neoplastic
lesions in the liver of MT1-HGF transgenic mice? C) What are the
molecular signals involved in the induction of HGF gene expression in
regenerating or xenobiotic treated liver in normal or the MT1-HGF
transgenic animals? Answers to these questions may provide further
insight to the molecular mechanisms by which tumor promoters and growth
factors induce chronic cell proliferation and cancer. Employing
techniques and specific molecular probes for HGF detection which are
well-established in our laboratory we will analyze the expression of HGF
and its receptor (the product of proto-oncogene cMET) in the MT1-HGF
transgenic mice treated with or without liver tumor promoters
phenobarbital, ciprofibrate, and the carcinogen Diethylnitrosamine to
determine whether there is any correlation between the high HGF
expression and histopathological abnormalities such as hyperplasia and
neoplasia in these animals. The expression of oncogenes c-myc, c-fos,
and c-jun which are believed to mediate the mitogenic response of several
polypeptide growth factors and also known to be transiently overexpressed
during liver regeneration and in some liver tumors (especially c-myc)
will be investigated in MT1-HGF transgenic and control mice treated with
or without liver tumor promoters. We will also attempt to establish
hepatocyte cell lines derived from the neoplastic and normal livers of
HGF-transgenic mice which may be suitable for in vitro mutagenesis
assays.