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Constructs
From the McArdle Laboratory for Cancer Research, Departments of Oncology and Pathology, The Medical School, University of Wisconsin, Madison, Wisconsin
Transgenic Sprague-Dawley rats expressing either human transforming
growth factor-
(TGF) or simian virus 40 large and small T antigen
(TAg), each under the control of the phosphoenolpyruvate
carboxykinase (PEPCK) promoter, were developed as an approach
to the study of the promotion of hepatocarcinogenesis in the presence
of a transgene regulatable by diet and/or hormones. Five lines of
PEPCK-TGF transgenic rats were established, each genetic
line containing from one to several copies of the transgene per haploid
genome. Two PEPCK-TAg transgenic founder rats were obtained,
each with multiple copies of the transgene. Expression of the transgene
was undetectable in the TGF transgenic rats and could not be induced
when the animals were placed on a high-protein,
low-carbohydrate diet. The transgene was found to be highly methylated
in all of these lines. No pathological alterations in the liver and
intestine were observed at any time (up to 2 years) during the lives of
these rats. One line of transgenic rats expressing the PEPCK-TAg
transgene developed pancreatic islet cell hyperplasias and
carcinomas, with few normal islets evident in the pancreas.
This transgene is integrated as a hypomethylated tandem array of 10 to
12 copies on chromosome 8q11. Expression of large T antigen is highest
in pancreatic neoplasms, but is also detectable in the normal
brain, kidney, and liver. Mortality is most rapid in
males, starting at 5 months of age and reaching 100% by 8
months. Morphologically, islet cell differentiation in the
tumors ranges from poor to well differentiated, with regions of
necrosis and fibrosis. Spontaneous metastasis of TAg-positive tumor
cells to regional lymph nodes was observed. These studies indicate the
importance of DNA methylation in the repression of specific transgenes
in the rat. However, the expression of the PEPCK-TAg induces
neoplastic transformation in islet cells, probably late in
neuroendocrine cell differentiation. T antigen expression during
neoplastic development may result in a pervasive change in the islet
cell growth properties with selection of a transformed phenotype as a
possible requirement for cell viability.
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