IEMURA Akihiro Kurume University, School of Medicine, Fellow, 医学部, 助手 (40212724)
YANO Hirohisa Kurume University, School of Medicine, Instructor, 医学部, 講師 (40220206)
|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1995 : ¥400,000 (Direct Cost : ¥400,000)
Fiscal Year 1994 : ¥1,400,000 (Direct Cost : ¥1,400,000)
1. Growth Stimulating Factors of Hepatocellular Carcinoma (HCC) Cells. We examined the effects of known growth factors on the proliferation of two clonally related HCC cell lines (HAK-1A & HAK-1B). HAK-1A is morphologically more differentiated and biologically less malignant than HAK-1B.The two HCC cell lines expressed the proteins and mRNAs of basic fibroblast growth factor (bFGF) and its receptor, FGFR.In vitro and in vivo experiments by using anti-bFGF neutralizing antibody and exogenous bFGF revealed that : (1) well-differentiated HCC cell line, HAK-1A,possessed a proliferation mechanism regulated by a paracrine mechanism, mediated by bFGF/FGFR ; (2) poorly differentiated HCC cell line, HAK-1B,possessed both autocrine and paracrine proliferatio mechanisms mediated by bFGF/FGFR ; and (3) bFGF/FGFR system also plays an important role in cell growth, but does not relate to angiogenesis in vivo. As to other growth factos and their receptors, the two cell lines expressed transforming growth factor (TGF) -alpha and its receptor, epidermal growth factor receptor (EGFR). Anti-EGFR neutralizing antibody showed growth suppressive effect on the cell lines, but anti-TGF-alpha neutralizing antibody showed no effect. This suggested involvement of the other EGFR ligands (EGF,heparin binding-EGF,amphiregulin, beta-cellulin etc.) in the HCC cell proliferation.
2. Growth Inhibition and Apoptosis Inducing Factors of HCC Cells. TGF-beta showed no significant effects on the two cell lines. As to the expression of Fas antigen, which is a apoptosis inducing protein, HAK-1B showed lower level of Fas antigen expression and resistance to anti-Fas-mediated apoptosis.
In conclusion, HCC cells may acquire more efficient cell proliferaton mechanisms (autocrine/paracrine) mediated by bFGF/FGFR in their dedifferentiation process. Also, loss of Fas system after clonal cell dedifferentiation is favorable for HCC cells to escape apoptosis.