Budget Amount *help |
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1997: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1996: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1995: ¥1,000,000 (Direct Cost: ¥1,000,000)
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Research Abstract |
Previously we found that the Ishikawa endometrial cancer cell line expresses macrophage colony-stimulating factor (M-CSF) and c-fms transcripts and that its proliferation is enhanced by the addition of recombinant M-CSF.Using retroviral infections to introduce and express exogenous c-fms genes in Ishikawa cells we also demonstrate proliferation to be partially inhibited by a dominant negative, mutant c-fms gene, yet enhanced approximately 3-fold by a normal c-fms gene, under conditions in which the only source of M-CSF was that produced by the cells. The data provide evidence for the existence of an active M-CSF/receptor loop in these endometrial cancer cells and suggests the possibility of such activity in tumors of the endometrium and ovary that aberrantly express M-CSF and c-fms genes. TNF-alpha, LPS and c-AMP elevating agents such as foskolin, cholera toxin, 8-brom-c-AMP,dibutyryl-c-AMP,and IBMX,inhibited Ishikawa cell growth dosedependently, whereas M-CSF levels in medium were increased by these agents. Phorbol ester, TPA stimulated cell proliferation though protein kinase C pathway. We also demonstrated that TNF-alpha receptor antibody, specifically activating 55kDa TNF-alpha receptor, and TNF-alpha analogue, binding to 55kDa TNF-alpha receptor, induced apoptosis in Ishikawa and ovarian cancer cell lines, using TUNEL method and flow cytomtry. TNF-alpha, LPS and c-AMP elevating agents inhibited cell proliferation in Ishikawa cells and ovarian cancer cells as well as in macrophage cell lines. It remains to be establishes whether these treatments caused a decrease in the expession of c-fms, and hence diminished sensitivity to M-CSF,despite the fact that the production of M-CSF was stimulated by these agents.
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