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Development the new cancer treatment targeting the regulation system of cancer stem cells

针对癌症干细胞调控系统开发新的癌症治疗方法

基本信息

批准号：
18390350
负责人：
NAKAMURA Masafumi
金额：
$ 10.98万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390350/
关键词：
cancer stem cell breast cancer colorectal cancer CD24-low CD44+side population Hedgehog DAPT Y-secretase 形態形成シグナル paclitaxel 薬剤耐性 Notch DAPT

项目摘要

(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 … More h.(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

（目的）肿瘤干细胞（Cancer stem cell，CSC）具有多药耐药的特点，被认为是造成肿瘤细胞异质性的爆发源。本研究的目的是阐明CSC的维持机制，并建立CSC的控制方法。（材料与方法）以乳腺癌和结直肠癌细胞株为材料，检测了在各种形态信号和抗癌药物的不同激活状态下，细胞株中CSC的数量。基于Hoechst 33342染色的强度（SP（侧群））或CD24-/低CD44+表达纯化CSC。我们分析了CSC中形态发生蛋白信号的活性。我们还检查了形态信号对CSC生长的意义。接下来，我们检查了DAPT（假定的结肠直肠CSC因子Notch信号的抑制剂）对抗癌剂敏感性的影响。此外，我们检测了针对Hedgehog信号通路受体Patched 1的抗体对CSC生长的影响。 ...更多信息 H.（结果）成功检测并纯化了乳腺癌细胞株SP组分和CD24-/low CD44+组分。SP组和CD24-/低CD44+组是CSC的主要组成部分，具有一定的耐药能力。刺猬（Hh）信号通路的转录激活因子Gli1在两种CSC组分中均上调。Hh信号传导活性的下调降低了整个所有细胞计数的CSC分数的比率。同时，Hh信号通路被认为是CSC因子，被ER激活，这是乳腺细胞分化的标志。Hh信号通路在癌症干细胞和分化的癌细胞中的这种复杂作用的意义必须进一步研究。DAPT是Y-分泌酶抑制剂和Notch信号的抑制剂，增加了结肠直肠癌细胞对抗癌剂的敏感性。进一步的研究表明，DAPT的这种抗癌能力与Notch无关，可能与APC状态有关。（结论）Hh信号通路可能是乳腺CSC维持所必需的。DAPT抑制了大肠癌的耐药能力，DAPT的靶点可能为阐明大肠癌干细胞的维持机制提供线索。少