Hormonal regulation of liver and tumor growth

Abstract

The aims of this thesis were to investigate the regulatory functions of interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a) on liver growth, and the importance of hepatocyte growth factor (HGF) and the HGF receptor (Met) for growth of mesenchyme-derived tumors. The studies on different types of liver growth, measured as weight, DNA and protein content, and DNA synthesis, were performed on mice lacking the IL-6 or the TNF receptor-1 gene back-crossed to the C57bl/6 strain. Liver weight was studied in mice of different ages, and liver regeneration was studied after two-thirds hepatectomy. Moreover, pharmacologically-induced growth of intact liver was studied using so-called primary liver growth promoters: the anti-androgen cyproterone acetate and the peroxisome proliferator nafenopin. Lack of IL-6 or TNF receptor-1 caused a retarded basal liver growth, and retarded regenerative liver growth after partial hepatectomy, but had no effect on pharmacologically-induced liver growth. We cloned the coding part of rat HGF receptor cDNA and determined the chromosomal localizations of the HGF and HGF receptor genes in the rat to chromosome 4q12 and q21, respectively. We found up to 80-fold amplification of the HGF receptor gene in DMBA-induced sarcomas in the rat, and corroboratively increased immunoreactive HGF receptor protein levels. In human musculoskeletal tumors, occurrence of the HGF receptor was significantly associated with tumor malignancy. We found no HGF receptor gene amplification in human tumors. Further, we found a short N-terminally truncated cytoplasmic HGF receptor fragment that was tyrosine phosphorylated in some malignant human tumors. This could represent a non ligand binding and auto-activated variant of the HGF receptor. Similar HGF receptor fragments have been shown to be tumor-promoting in experimental studies but have not been found in human tumors before.