Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling
Chloroquine Targets Pancreatic Cancer Stem Cells via Inhibition of CXCR4 and Hedgehog Signaling
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DOI：
10.1158/1535-7163.mct-13-0948
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发表时间：
2014-07-01
影响因子：
5.7
通讯作者：
Heeschen, Christopher
中科院分区：
文献类型：
--
作者：
Balic, Anamaria;Draeby Sorensen, Morten;Heeschen, Christopher
胰管腺癌是最致命的肿瘤之一，其特点是高致瘤性和转移性肿瘤干细胞（CSC）。CSCs逃避现有的治疗，这些治疗优先针对高增殖和更分化的后代，留下CSCs作为疾病复发的假定来源。因此，为了确定潜在的更有效的治疗方案，我们筛选了已建立的和新的化合物，以在体外消除原发性胰腺癌（干细胞）细胞和体内相应的患者来源的胰腺癌组织异种移植物中的CSCs。有趣的是，我们发现抗疟药氯喹的体外治疗显著降低了CSCs，在大量胰腺癌中转化为体内致瘤性和侵袭性降低。体内治疗联合吉西他滨能够更有效地消除已建立的肿瘤并提高总生存期。氯喹的抑制作用与抑制自噬无关，而是由于抑制CXCL12/CXCR4信号通路，导致ERK和STAT3磷酸化降低。此外，氯喹通过减少Smoothened的产生，显示出对刺猬信号的有效抑制，从而显著降低了音刺猬诱导的趋化性，并下调了CSCs和周围基质中下游靶点的表达。我们的研究表明，通过迄今未报道的效果，氯喹是化疗的有效辅助治疗，提供更有效的肿瘤消除和提高治愈率。氯喹的成功应用可能有助于更迅速地改善胰腺癌患者的不良预后，值得在临床环境中进一步探索。(c) 2014年aacr。
Pancreaticductal adenocarcinoma is one of the deadliest carcinomas andis characterized by highly tumorigenic and metastatic cancer stem cells (CSC). CSCs evade available therapies, which preferentially target highly proliferative and more differentiated progenies, leaving behind CSCs as a putative source for disease relapse. Thus, to identify potentially more effective treatment regimens, we screened established and new compounds for their ability to eliminate CSCs in primary pancreatic cancer (stem) cells in vitro and corresponding patient-derived pancreatic cancer tissue xenografts in vivo. Intriguingly, we found that in vitro treatment with the antimalarial agent chloroquine significantly decreased CSCs, translating into diminished in vivo tumorigenicity and invasiveness in a large panel of pancreatic cancers. In vivo treatment in combination with gemcitabine was capable of more effectively eliminating established tumors and improved overall survival. The inhibitory effect of chloroquine was not related to inhibition of autophagy, but was due to inhibition of CXCL12/CXCR4 signaling, resulting in reduced phosphorylation of ERK and STAT3. Furthermore, chloroquine showed potent inhibition of hedgehog signaling by decreasing the production of Smoothened, translating into a significant reduction in sonic hedgehog-induced chemotaxis and downregulation of downstream targets in CSCs and the surrounding stroma. Our study demonstrates that via to date unreported effects, chloroquine is an effective adjuvant therapy to chemotherapy, offering more efficient tumor elimination and improved cure rates. Chloroquine should be further explored in the clinical setting as its success may help to more rapidly improve the poor prognosis of patients with pancreatic cancer. (C) 2014 AACR.