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）以具有多重耐药性为特征的癌症干细胞（CSC）被认为是产生癌细胞异质性的爆发源。本研究的目的是阐明维持CSC的机制并建立控制方法。 CSC。(材料和方法) 对于乳腺癌和结直肠癌细胞株，我们检查了在各种形态发生素信号和抗癌剂的不同激活状态下，细胞株中CSC的数量。根据 Hoechst 33342 染色（SP（侧群））或 CD24-/低 CD44+ 表达的强度纯化 CSC。我们还分析了 CSC 中形态发生素信号的活性。 DAPT（假设的结直肠 CSC 因子 Notch 信号的抑制剂）对抗癌剂敏感性的影响此外，我们检查了针对其产生的抗体的效果。 Patched1，Hedgehog信号通路受体，对CSC生长的影响... 更多 h.(结果) 我们成功检测和纯化了乳腺癌细胞株的SP组分和CD24-/低CD44+组分这两种CSC组分，SP组分和CD24。 -/低 CD44+ 比例，共享主要群体并具有耐药能力，Gli1（Hedgehog (Hh) 信号通路的 trance 激活剂）在两者中均上调。 CSC 分数。Hh 信号活性的下调降低了 CSC 分数占全部细胞计数的比例，同时，Hh 信号通路（所谓的 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癌细胞中的这种复杂作用有待进一步研究，DAPT（Y 分泌酶抑制剂和 Notch 信号的抑制剂）增加了结直肠癌细胞对 Hh 信号通路的敏感性。进一步研究发现DAPT的这种抗癌能力与Notch无关，可能与APC状态有关。(结论)Hh信号通路可能对维持乳腺CSC的耐药性至关重要。结直肠癌的能力和DAPT的靶点可能为阐明结直肠CSC的维持系统提供线索。