IN-VIVO INFUSION OF GROWTH-FACTORS ENHANCES THE MITOGENIC RESPONSE OFRAT HEPATIC DUCTAL (OVAL) CELLS AFTER ADMINISTRATION OF 2-ACETYLAMINOFLUORENE

Expression of several growth factors is elevated in rat liver, after i nduction of oval cell proliferation by chemical carcinogens. However, the exact roles played by individual factors are not defined, We infus ed and examined the effects of epidermal growth factor (EGF) and hepat ocyte growth factor (HGF) on the proliferation of ductal and periducta l cells after their activation with 2-acetylaminofluorene (2-AAF). Fur thermore, we included studies on urokinase-type plasminogen activator (uPA), because Northern blot analysis showed a strong coincidence of u PA expression with oval cell proliferation, Low doses of 2-AAF were us ed to activate ductal and periductal cells, whereafter growth factors were infused. Infusion of EGF, HGF, uPA, or any combination thereof fo r up to 7 days resulted in increased numbers of [H-3]thymidine-labeled ductal and periductal cells expanding into the liver acinus, Although the growth factors all increased the number of labeled cells, they pr eferentially acted on different cell populations. Although exposure to 2-AAF alone or combined with infusion of HGF resulted in proliferatio n of almost equal numbers of ductal and Ito cells, infusion of EGF and any combination hereof resulted in 75% to 80% of labeled cells having a ductal phenotype. Also, infusion of EGF and HGF resulted in decreas ed numbers of cells undergoing apoptosis in response to 2-AAF, Our res ults demonstrate that, although 2-AAF acts as a mitogenic stimulus for ductal and periductal cells, growth factors are necessary for surviva l, motility, and expansion of these cells into the liver acini.