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Clodronate Liposomes氯膦酸盐脂质体助力前列腺癌骨转移模型巨噬细胞研究
中文摘要：
转移性去势抵抗性前列腺癌 （PC） 是 PC 的最后阶段，对雄激素剥夺疗法 （ADT） 产生耐药性。尽管对疾病机制的理解取得了进展，但转移性微环境对 ADT 耐药的具体贡献在很大程度上仍然未知。目前的研究确定，巨噬细胞是患者骨转移性 PC 的主要微环境成分。使用一种新的体内模型，我们证明巨噬细胞通过诱导 ECM 受体基因表达的伤口愈合样反应对恩杂鲁胺耐药至关重要。从机制上讲，巨噬细胞通过细胞因子激活素 A 驱动耐药性，从而在 PC 细胞中诱导纤连蛋白 （FN1）-整合素 α 5 （ITGA5）-酪氨酸激酶 Src （SRC） 信号级联反应。这种新机制得到了患者转录组学数据集的生物信息学分析的强烈支持。此外，使用新型特异性抑制剂的巨噬细胞耗竭或 SRC 抑制显着抑制了耐药生长。总之，我们的研究结果阐明了巨噬细胞诱导的转移性 PC 抗雄激素耐药的新机制，以及治疗这种致命疾病的有前途的治疗方法。
英文摘要：
Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing–like response of ECM–receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)–tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease.
论文信息：
论文题目： Macrophages promote anti-androgen resistance in prostate cancer bone disease
期刊名称：JEM- J Exp Med
时间期卷：J Exp Med (2023) 220 (4): e20221007.
在线时间：2022年2月7日
DOI：doi.org/10.1084/jem.20221007
Clodronate Liposomes氯膦酸盐脂质体助力前列腺癌骨转移模型巨噬细胞研究，Liposoma巨噬细胞清除剂Clodronate Liposomes见刊于JEM：
Liposoma巨噬细胞清除剂Clodronate Liposomes氯膦酸二钠脂质体的材料和方法：
JEM期刊巨噬细胞清除解决方案
Drug treatments
Vehicle and enzalutamide (30 mg/kg body weight), SRC inhibitor eCF506 (20 mg/kg body weight) was given via daily oral gavage; L-Clod/PBS (1 mg/mouse, twice a week) were administered by i.v. injection; DT or control Glu52-DT (25 μg/kg body weight, every other day), anti-Ly-6G depleting Abs (200 μg/mouse, every other day), activin-A receptor inhibitor SB-505124 (5 mg/kg body weight, every other day) were delivered by i.p. injection. In some experiments, mice continuously received doxycycline diet (625 mg/kg). Enzalutamide was synthesized by chemical core at Memorial Sloan Kettering Cancer Center; eCF506 was kindly provided by A. Unciti-Broceta; L-Clod/PBS was from Liposoma; anti-Ly-6G Abs (clone #1A8) were from BioxCell; activin-A receptor inhibitor SB-505124 was from Selleckchem; and DT/Glu52-DT was from Sigma-Aldrich.
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