Chemotherapy Sensitizes Therapy-Resistant Cells to Mild Hyperthermia by Suppressing Heat Shock Protein 27 Expression in Triple-Negative Breast Cancer.
Chemotherapy Sensitizes Therapy-Resistant Cells to Mild Hyperthermia by Suppressing Heat Shock Protein 27 Expression in Triple-Negative Breast Cancer.
复制标题
化疗通过抑制三阴性乳腺癌中的热休克蛋白 27 表达，使治疗耐药细胞对轻度高热敏感
DOI：
10.1158/1078-0432.ccr-17-3872
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Shen H
中科院分区：
文献类型：
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作者：
Mu C;Wu X;Zhou X;Wolfram J;Shen J;Zhang D;Mai J;Xia X;Holder AM;Ferrari M;Liu X;Shen H
三阴性乳腺癌（TNBC）是一种临床侵袭性疾病，预后差。传统的化疗通常能够缩小肿瘤肿块，但往往不能完全根除癌症干细胞（CSCs），这是导致复发和频繁转移的高风险因素。在这项研究中，我们检测了CSCs的热敏性，开发了一种能够同时消除大部分癌细胞和CSCs的方法，并研究了潜在的机制。我们设计了一个由金纳米颗粒包覆的多孔硅微粒（AuPSM）组成的平台，该平台还装载了多西紫杉醇胶束（mDTX），通过近红外刺激AuPSM，通过温和的高温释放mDTX和CSCs，可以同时杀死大部分癌细胞。此外，我们还研究了热休克蛋白在致敏CSC杀伤中的作用。最后，我们将mdtx负载的AuPSM应用于SUM159和4T1原位肿瘤小鼠，并评估肿瘤生长和肿瘤转移情况。MDA-MB-231和SUM159 TNBC细胞经mDTX负载的AuPSM和轻度热疗处理后，其乳腺球形成的效率明显低于单独使用mDTX或轻度热疗的细胞。联合治疗也完全抑制了SUM159原位肿瘤生长和4T1肿瘤转移。从机制上讲，DTX治疗抑制了包括csc在内的癌细胞中热休克蛋白27的表达，使细胞对轻度高温敏感。我们的研究结果表明，化疗使CSC对轻度高温敏感。我们已经开发出一种有效的治疗方法来消除TNBC中的治疗耐药细胞。
Triple-negative breast cancer (TNBC) is a clinically aggressive disease with poor prognosis. Conventional chemotherapeutics are generally able to shrink the tumor mass, but often fail to completely eradicate cancer stem-like cells (CSCs) that are responsible for high risk of relapse and frequent metastases. In this study, we examined thermal sensibility of CSCs, developed an approach that enabled concurrent elimination of both the bulk of cancer cells and CSCs, and investigated the underlying mechanism. We designed a platform consisting of gold nanoparticle-coated porous silicon microparticle (AuPSM) that was also loaded with docetaxel micelles (mDTX) to enable concurrent killing of the bulk of cancer cells by released mDTX and CSCs by mild hyperthermia upon stimulation of AuPSM with near infrared. In addition, we examined the role of heat shock proteins in sensitizing CSC killing. Finally, we applied mDTX-loaded AuPSM to treat mice with SUM159 and 4T1 orthotopic tumors, and evaluated tumor growth and tumor metastasis. MDA-MB-231 and SUM159 TNBC cells treated with mDTX-loaded AuPSM and mild hyperthermia displayed significantly reduced efficiencies in mammosphere formation than those treated with mDTX alone or mild hyperthermia alone. Combination treatment also completely inhibited SUM159 orthotopic tumor growth and 4T1 tumor metastasis. Mechanistically, DTX treatment suppressed expression of heat shock protein 27 in cancer cells including the CSCs, rendering cells sensitive to mild hyperthermia. Our results indicate that chemotherapy sensitizes CSC to mild hyperthermia. We have developed an effective therapeutic approach to eliminate therapy-resistant cells in TNBC.