中文摘要：
轉移性去勢抵抗性前列腺癌 （PC） 是 PC 的最后階段，對雄激素剝奪療法 （ADT） 產生耐藥性。盡管對疾病機制的理解取得了進展，但轉移性微環境對 ADT 耐藥的具體貢獻在很大程度上仍然未知。目前的研究確定，巨噬細胞是患者骨轉移性 PC 的主要微環境成分。使用一種新的體內模型，我們證明巨噬細胞通過誘導 ECM 受體基因表達的傷口愈合樣反應對恩雜魯胺耐藥至關重要。從機制上講，巨噬細胞通過細胞因子激活素 A 驅動耐藥性，從而在 PC 細胞中誘導纖連蛋白 （FN1）-整合素 α 5 （ITGA5）-酪氨酸激酶 Src （SRC） 信號級聯反應。這種新機制得到了患者轉錄組學數據集的生物信息學分析的強烈支持。此外，使用新型特異性抑制劑的巨噬細胞耗竭或 SRC 抑制顯著抑制了耐藥生長。總之，我們的研究結果闡明了巨噬細胞誘導的轉移性 PC 抗雄激素耐藥的新機制，以及治療這種致命疾病的有前途的治療方法。
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.
論文信息：
論文題目： Macrophages promote anti-androgen resistance in prostate cancer bone disease
期刊名稱：JEM- J Exp Med
時間期卷：J Exp Med (2023) 220 (4): e20221007.
在線時間：2022年2月7日
DOI：doi.org/10.1084/jem.20221007
Clodronate Liposomes氯膦酸鹽脂質體助力前列腺癌骨轉移模型巨噬細胞研究，Liposoma巨噬細胞清除劑Clodronate Liposomes見刊于JEM：
Liposoma巨噬細胞清除劑Clodronate Liposomes氯膦酸二鈉脂質體的材料和方法：
JEM期刊巨噬細胞清除解決方案
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.
