for survival, motility, and expansion of these cells into Expression of several growth factors is elevated in rat the liver acini. (HEPATOLOGY 1996;23:71-79.) liver, after induction of oval cell proliferation by chemical carcinogens. However, the exact roles played by individual factors are not defined. We infused and examined
Although altered expression of growth factors is a the effects of epidermal growth factor (EGF) and hepatowell-known response in normal hepatic liver regeneracyte growth factor (HGF) on the proliferation of ductal tion as well as after chemical injury, the exact role of and periductal cells after their activation with 2-acetylindividual growth factors in the processes has yet to aminofluorene (2-AAF). Furthermore, we included studbe defined. A number of experimental models exist in ies on urokinase-type plasminogen activator (uPA), which the proliferation of different cell types of the because Northern blot analysis showed a strong coliver can be preferentially induced. Although a twoincidence of uPA expression with oval cell proliferation.
thirds partial hepatectomy (PH) induces a proliferative
Low doses of 2-AAF were used to activate ductal and periductal cells, whereafter growth factors were in-response of all cell types in the liver, including preexfused. Infusion of EGF, HGF, uPA, or any combination isting hepatocytes, a variety of chemical carcinogens thereof for up to 7 days resulted in increased numbers and toxic agents have been shown to induce extensive of [ 3 H]thymidine-labeled ductal and periductal cells exproliferation of small ductal-like epithelial cells, the panding into the liver acinus. Although the growth facso-called oval cells. 1 Several growth factors, including tors all increased the number of labeled cells, they prefepidermal growth factor (EGF), transforming growth erentially acted on different cell populations. Although factor a (TGF-a), and hepatocyte growth factor (HGF), exposure to 2-AAF alone or combined with infusion of are considered to play important roles in the response
HGF resulted in proliferation of almost equal numbers
of the liver to both surgical and chemical injury. 2
EGF of ductal and Ito cells, infusion of EGF and any combina-
and TGF-a bind to the epidermal growth factor reception hereof resulted in 75% to 80% of labeled cells having a ductal phenotype. Also, infusion of EGF and HGF re-tor (EGFR), which mediates their effects through its sulted in decreased numbers of cells undergoing tyrosine kinase activity. 3 Although EGF is produced apoptosis in response to 2-AAF. Our results demonstrate in extrahepatic tissues and may act in an endocrine that, although 2-AAF acts as a mitogenic stimulus for fashion, TGF-a appears to be an important autocrine ductal and periductal cells, growth factors are necessary regulator of hepatic cell replication. [4][5][6] Conversely, HGF, which binds to another tyrosine kinase receptor, the c-met receptor, is produced both at extrahepatic sites and by nonparenchymal liver cells. 7,8 After chemi-Abbreviations: PH, partial hepatectomy; PBS, phosphate buffered saline; cal injury, HGF production by nonparenchymal hepatic EGF, epidermal growth factor; TGF-a, transforming growth factor a; HGF, Ito cells is greatly increased. 9 In contrast, after a simple hepatocyte growth factor; PD, periductal area; uPA, urokinase-type plasminogen activator; 2-AAF, 2-acetylaminofluorene; g-GT, g-glutamyl transpepti-two-thirds PH, there is a rapid increase in the serum dase; mRNA, messenger RNA; OV-6, oval cells. concentration of HGF, followed later by synthesis in From the Laboratory of Experimental Carcinogenesis, National Cancer Inthe liver. 10 Because the precursor pro-HGF is cleaved to