Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer
Combined Targeted Treatment to Eliminate Tumorigenic Cancer Stem Cells in Human Pancreatic Cancer
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DOI：
10.1053/j.gastro.2009.05.053
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
Heeschen, Christopher
中科院分区：
文献类型：
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作者：
Mueller, Maria-Theresa;Hermann, Patrick C.;Heeschen, Christopher
背景与目的：胰腺癌仅含有致瘤性癌症干细胞（CSC），其对化疗具有高度抵抗力，导致吉西他滨治疗期间CSC数量相对增加。分别通过声波刺猬和哺乳动物雷帕霉素靶点 (mTOR) 发出的信号可能对于 CSC 的自我更新至关重要，并且可以代表新型治疗方式的假定靶点。方法：我们使用胰腺癌的体外和体内模型来检查 sonic hedgehog 抑制（环巴明/CUR199691）和 mTOR 阻断（雷帕霉素）对致瘤 CSC 群体的影响。结果：令人惊讶的是，环巴明和雷帕霉素单独使用或作为化疗的补充都无法有效减少 CSC 库。只有同时抑制这两种途径并结合化疗才能将 CSC 的数量减少到体外和体内几乎不可检测的水平。最重要的是，在患有源自患者的胰腺肿瘤的小鼠体内施用这种三重组合具有合理的耐受性，并转化为显着延长的长期生存。结论：将 sonic hidehog 和 mTOR 信号传导联合阻断以及标准化疗能够消除胰腺 CSC。对这种有希望的方法的进一步临床前研究可能会导致开发出一种新的治疗策略，以改善胰腺癌患者的破坏性预后。
BACKGROUND & AIMS: Pancreatic cancers contain exclusively tumorigenic cancer stem cells (CSCs), which are highly resistant to chemotherapy, resulting in a relative increase in CSC numbers during gemcitabine treatment. Signaling through sonic hedgehog and mammalian target of rapamycin (mTOR), respectively, may be essential for CSC self-renewal and could represent putative targets for novel treatment modalities. METHODS: We used in vitro and in vivo models of pancreatic cancer to examine the effects of sonic hedgehog inhibition (cyclopamine/CUR199691) and mTOR blockade (rapamycin) on the tumorigenic CSC population. RESULTS: Surprisingly, neither cyclopamine nor rapamycin alone or as supplements to chemotherapy were capable of effectivety diminishing the CSC pool. Only the combined inhibition of both pathways together with chemotherapy reduced the number of CSCs to virtually undetectable levels in vitro and in vivo. Most importantly, in vivo administration of this triple combination in mice with established patient-derived pancreatic tumors was reasonably tolerated and translated into significantly prolonged long-term survival. CONCLUSIONS: The combined blockade of sonic hedgehog and mTOR signaling together with standard chemotherapy is capable of eliminating pancreatic CSCs. Further preclinical investigation of this promising approach may lead to the development of a novel therapeutic strategy to improve the devastating prognosis of patients with pancreatic cancer.