Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer
Reciprocal Network between Cancer Stem-Like Cells and Macrophages Facilitates the Progression and Androgen Deprivation Therapy Resistance of Prostate Cancer
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癌症干细胞样细胞和巨噬细胞之间的互惠网络促进前列腺癌的进展和雄激素剥夺疗法的抵抗。
DOI：
10.1158/1078-0432.ccr-18-0461
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发表时间：
2018-09-15
影响因子：
11.5
通讯作者：
Sun, Ying-Hao
中科院分区：
文献类型：
--
作者：
Huang, Hai;Wang, Chao;Sun, Ying-Hao
目的：癌干细胞（Cancer stem-like cells， CSC）参与前列腺癌的进展和雄激素剥夺治疗（ADT）的抵抗。由于CSCs依赖于其特定的生态位，包括肿瘤相关巨噬细胞（TAM），阐明CSCs与TAM之间的网络可能有助于有效抑制前列腺癌的进展和ADT耐药性。实验设计：通过RNA测序、共免疫沉淀、染色质免疫沉淀和其他分析来评估维持前列腺癌CSCs干细胞样特征的潜在细胞内机制。采用共培养系统和细胞因子抗体阵列来检测CSCs和tam之间的相互作用网络。此外，我们建立了原位前列腺癌模型，以评估CSCs联合靶向及其与tam相互作用对ADT耐药的体内影响。结果：自噬相关基因7 （Autophagy-related gene 7, ATG7）通过β-catenin促进OCT4转录，β-catenin结合OCT4启动子，促进前列腺癌CSC特征，包括自我更新、肿瘤起始和耐药。此外，CSCs通过将单核细胞/巨噬细胞培养为tam重塑其特定的生态位，并且csc培养的tam通过il - 6/STAT3相互促进CSCs的干细胞样特性、进展和前列腺癌的ADT耐药。此外，通过抑制ATG7/OCT4和IL6受体联合靶向CSCs及其与tam的相互作用，有效改善了原位前列腺癌模型中ADT耐药性。结论：靶向CSCs及其利基可能比单独靶向CSCs更有效，为改善前列腺癌ADT耐药提供了一种合理的方法。临床癌症研究；24 (18);4612 - 26所示。AACR©2018。
Purpose: Cancer stem-like cells (CSC) contribute to the progression and androgen deprivation therapy (ADT) resistance of prostate cancer. As CSCs depend on their specific niche, including tumor-associated macrophages (TAM), elucidating the network between CSCs and TAMs may help to effectively inhibit the progression and ADT resistance of prostate cancer. Experimental Design: The underlying intracellular mechanism that sustains the stem-like characteristics of CSCs in prostate cancer was assessed via RNA sequencing, co-immunoprecipitation, chromatin immunoprecipitation, and other assays. A coculture system and cytokine antibody arrays were used to examine the interaction network between CSCs and TAMs. In addition, an orthotopic prostate cancer model was established to evaluate the in vivo effects of the combined targeting of CSCs and their interaction with TAMs on ADT resistance. Results: Autophagy-related gene 7 (ATG7) facilitated the transcription of OCT4 via β-catenin, which binds to the OCT4 promoter, promoting CSC characteristics in prostate cancer, including self-renewal, tumor initiation, and drug resistance. In addition, CSCs remodeled their specific niche by educating monocytes/macrophages toward TAMs, and the CSC-educated TAMs reciprocally promoted the stem-like properties of CSCs, progression and ADT resistance of prostate cancer via IL6/STAT3. Furthermore, the combined targeting of CSCs and their interaction with TAMs by inhibiting ATG7/OCT4 and IL6 receptor effectively ameliorated ADT resistance in an orthotopic prostate cancer model. Conclusions: Targeting CSCs and their niche may prove to be a more powerful strategy than targeting CSCs alone, providing a rational approach to ameliorating ADT resistance in prostate cancer. Clin Cancer Res; 24(18); 4612–26. ©2018 AACR.