| Budget Amount *help |
¥17,160,000 (Direct Cost: ¥15,600,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2007: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
Fiscal Year 2006: ¥10,400,000 (Direct Cost: ¥10,400,000)
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| Research Abstract |
(Purpose) Cancer stem cell (CSC), characterized by the ability of multi-drug resistance, assumed as outbreak source to create heterogeneity of cancer cells. The purpose of this research is to elucidate the mechanism of maintaining CSC and to establish control method for CSC.
(Materials and a methods) With breast cancer and colo-rectal cancer cell strains, we examined the number of CSCs in the strains under the different activation state of the various morphogen signals and anticancer agents. CSCs were purified based on the intensity of Hoechst 33342 staining (SP (side population)) or CD24-/lowCD44+ expression. We analyzed activity of the morphogen signals in CSC. We also checked the significance of morphogen signals on CSC growth. Next we examined influence of DAPT, suppressor of assumed colo-rectal CSC factor Notch signal, on sensitivity of anti-cancer agent. Furthermore, we inspected the effect of antibodies raised against Patched1, receptor of Hedgehog signaling pathway, on CSC growt
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(Results) We succeeded in the detection and purification of SP fraction and CD24-/low CD44+ fraction of breast cancer cell strain. These two CSC fractions, SP fraction and CD24-/low CD44+ fraction, shared major population and had the drug resistant ability. Gli1, trancactivator of the Hedgehog (Hh) signaling pathway, was up-regulated in both CSC fractions. Down-regulation of the Hh signaling activity reduced the ratio of the CSC fractions of the whole all cell counts. Meanwhile, Hh signaling pathway, supposed CSC factor, was activated by ER, a landmark of the breast cell differentiation. The significance of this complicated role of Hh signaling pathway in both cancer stem cells and differentiated cancer cells has to be further examined. DAPT, the suppressor of Y-secretase inhibitor and the Notch signal, increased the sensitivity of colo-rectal cancer cells to the anti-cancer agent. Further examination revealed that this anti-cancer ability of DAPT is unrelated to Notch, and may be involved in APC status.
(Conclusion) Hh signaling pathway may be essential for the maintenance of breast CSC. DAPT suppressed the drag resistance ability of colorectal cancer and the target of DAPT may give clues to elucidate the maintenance system of colorectal CSC. Less
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