Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells
Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells
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DOI：
10.1002/ijc.27595
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发表时间：
2012-12-15
影响因子：
6.4
通讯作者：
Roidl, Andreas
中科院分区：
文献类型：
--
作者：
Oak, Prajakta S.;Kopp, Florian;Roidl, Andreas
癌症治疗成功的一个主要障碍是化疗耐药的发生。在化疗后存活并导致肿瘤复发的癌细胞被称为癌症干细胞，可以通过某些干细胞标志物水平的升高来识别。根除这种细胞群体是癌症治疗的首要目标。在这里，我们报告了MCF-7乳腺干细胞标记物水平的升高。同样，HER2的上调及其在乳房单个细胞中的差异表达也被观察到。对HER2(高)和HER2(低)细胞的分选显示，干细胞标记NANOG、OCT4和SOX2在HER2(低)细胞组分中上调。相应地，HER2(低)细胞也表现出增殖减少、导管样突起和基质细胞中克隆数量的增加。皮下注射HER2(低)分选细胞的异种移植与HER2(高)组分形成的肿瘤相比，肿瘤发病较早，但生长较慢，干细胞标志物增加。用盐霉素治疗乳房减少了SOX2的表达，这表明肿瘤干细胞是有选择性的靶点。然而，曲妥珠单抗并没有减少SOX2在乳房中的表达。此外，曲妥珠单抗和盐霉素联合治疗乳房气肿优于两种药物单独治疗。因此，以表达HER2的肿瘤为靶点进行抗HER2治疗并不一定会消除癌症干细胞，并可能导致更具侵袭性的癌细胞表型。我们的研究证明了HER2阳性细胞和癌症干细胞的有效杀伤，从而为新的联合治疗策略打开了可能性。
A major obstacle in the successful treatment of cancer is the occurrence of chemoresistance. Cancer cells surviving chemotherapy and giving rise to a recurrence of the tumor are termed cancer stem cells and can be identified by elevated levels of certain stem cell markers. Eradication of this cell population is a priority objective in cancer therapy. Here, we report elevated levels of stem cell markers in MCF-7 mammospheres. Likewise, an upregulation of HER2 and its differential expression within individual cells of mammospheres was observed. Sorting for HER2(high) and HER2(low) cells revealed an upregulation of stem cell markers NANOG, OCT4 and SOX2 in the HER2(low) cell fraction. Accordingly, HER2(low) cells also showed reduced proliferation, ductal-like outgrowths and an increased number of colonies in matrigel. Xenografts from subcutaneously injected HER2(low) sorted cells exihibited earlier onset but slower growth of tumors and an increase in stem cell markers compared to tumors developed from the HER2(high) fraction. Treatment of mammospheres with salinomycin reduced the expression of SOX2 indicating a selective targeting of cancer stem cells. Trastuzumab however, did not reduce the expression of SOX2 in mammospheres. Furthermore, a combinatorial treatment of mammospheres with trastuzumab and salinomycin was superior to single treatment with each drug. Thus, targeting HER2 expressing tumors with anti-HER2 therapies will not necessarily eliminate cancer stem cells and may lead to a more aggressive cancer cell phenotype. Our study demonstrates efficient killing of both HER2 positive cells and cancer stem cells, hence opening a possibility for a new combinatorial treatment strategy.