阻断神经内分泌分化与巨噬细胞的反馈回路提高比卡鲁胺(MDV3100)对前列腺癌的疗效

文献 Blocking the Feedback Loop between Neuroendocrine Differentiation and Macrophages Improves the Therapeutic Effects of Enzalutamide (MDV3100) on Prostate Cancer. 发表在 Clinical Cancer Research 原文链接

Abstract:

Purpose: 

Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.


Experimental Design: 

The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using in vitro cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the in vivo effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.


Results: 

High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.


Conclusions: 

Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer.


摘要:

目的:

用于前列腺癌的雄激素阻断治疗(ADT)包括比卡鲁胺,ADT和神经内分泌分化(NED)、肿瘤相关巨噬细胞(TAM)有关。本研究旨在探讨比卡鲁胺诱导的NED、TAMS之间的联系及其相关机制。


方法:

以前列腺癌组织、耐比卡鲁胺的小鼠异种移植和共培养系统为研究对象,采用IHC法研究了比卡鲁胺诱导的NED与TAMS的关系。采用体外细胞因子抗体阵列法、ELISAs法、染色质免疫沉淀法等方法评价其作用机制。建立原位前列腺癌小鼠模型,评价IL6受体(IL6R)和高迁移率族蛋白1(HMGB1)的体内联合抑制作用。


结果:

CD163在ADT治疗的前列腺癌或高水平的神经元特异性烯醇化酶(NSE)和嗜铬粒蛋白A(CHGA)的去势抵抗性前列腺癌(CRPC)和比卡鲁胺耐药异种移植物中高度表达,说明NED和TAMS在比卡鲁胺抗癌中发挥重要作用。具体而言,比卡鲁胺诱导HMGB1表达促进TAM聚集和极化,通过β-连环蛋白稳定化驱动NED的发生。HMGB1激活TAMS分泌大量IL6,从而促进比卡鲁胺诱导NED发生并且直接促进STAT3诱导HMGB1转录。在前列腺癌小鼠模型中,通过联合妥西利和HMGB1基因敲除来抑制IL6或STAT3通路,从而抑制比卡鲁胺的诱导作用。


结论:

比卡鲁胺使HMGB1水平升高,促进TAM聚集和极化。此外,HMGB1激活TAMS分泌IL6促进了前列腺癌中比卡鲁胺诱导NED的发生,形成了前列腺癌NED与TAMS之间的正反馈调节。联合使用IL6R和HMGB1抑制剂可作为治疗晚期或转移性前列腺癌比卡鲁胺耐药性的新方法。


使用试剂原文信息:The IL-6, HMGB1 and PSA levels in serum or cell culture medium were measured using ELISA Kit for Interleukin-6 (SEA079Hu, Cloud-Clone Corp, Houston, Texas, Houston, Texas, USA), ELISA Kit for High Mobility Group Protein 1 (SEA399Hu, Cloud-Clone Corp) and PSA Quantikine ELISA Kit (DKK300, R&D Systems, Houston, Texas, USA) respectively, according to the manufacturer’s instructions.


文献相关产品 SEA399HuSEA079Hu 由云克隆研发生产