Development of dual targeting therapy for cancer stem cells and niche

癌症干细胞和微环境双靶向疗法的开发

基本信息

批准号：
21591213
负责人：
KOBUNE Masayoshi
金额：
$ 2.91万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21591213/
关键词：
癌内科シグナル伝達臨床発現制御

项目摘要

Aberrant reactivation of Hedgehog(Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of Hh signaling system in bone marrow(BM) microenvironment in the development of myeloid neoplasm has remained unclear. In this study, we assessed the expression of Hh related proteins in normal human CD34+cells, CD34+leukemic/dysplastic cells and BM stromal cells. Both Indian hedgehog(Ihh) and its signal transducer, SMO were expressed in CD34+acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) derived cells, suggesting that Ihh could effect in autocrine manner. Remarkably, the intrinsic Hh signaling inhibitor, human hedgehog-interacting protein(HHIP) expression in AML/MDS-associated stromal cells was drastically lower than that in healthy donor derived stromal cells. Moreover, the HHIP expression level in BM stromal cells highly correlated with supporting activity of SMO+leukemic cells. Demethylating agent 5-aza-dC rescued the HHIP expression via demethylation of HHIP gene and reduced the leukemia-supporting activity of AML/MDS-associated stromal cells. This effect of 5-aza-dC could be negated by HHIP shRNA transfer into stromal cells. Interestingly, HHIP-reduced stromal cells preferentially migrated toward Ihh-releasing leukemic cells. These results indicate that suppression of stromal HHIP expression could be involved in the progression of AML/MDS.

在包括癌症干细胞在内的多种人类癌症中，已经描述了刺猬（HH）信号的异常重新激活。但是，HH信号系统参与骨髓（BM）微环境在髓样肿瘤的发展中尚不清楚。在这项研究中，我们评估了正常人CD34+细胞，CD34+白血病/异常细胞和BM基质细胞中HH相关蛋白的表达。印度刺猬（IHH）及其信号传感器SMO均在CD34+急性髓样白血病（AML）和骨髓增生性综合征（MDS）衍生的细胞中表达，这表明IHH可以自动分泌方式作用。值得注意的是，固有的HH信号抑制剂，AML/MDS相关的基质细胞中的人刺猬相互作用蛋白（HHIP）表达大大低于健康供体衍生的基质细胞中的人。此外，BM基质细胞中的HHOH表达水平与SMO+白血病细胞的支持高度相关。脱甲基剂5-Aza-DC通过HHIP基因的脱甲基化营救了HOHH的表达，并降低了AML/MDS相关的基质细胞的白血病支持活性。 5-aza-DC的这种效果可以通过将shRNA转移到基质细胞中否定。有趣的是，HOPS减少的基质细胞优先迁移到富含IHH的白血病细胞。这些结果表明，抑制基质HHOH表达可能与AML/MD的进展有关。