中文摘要：
轉(zhuǎn)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(chǎn)生耐藥性。盡管對疾病機制的理解取得了進展，但轉(zhuǎn)移性微環(huán)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(xì)胞是患者骨轉(zhuǎn)移性 PC 的主要微環(huán)境成分。使用一種新的體內(nèi)模型，我們證明巨噬細(xì)胞通過誘導(dǎo) ECM 受體基因表達的傷口愈合樣反應(yīng)對恩雜魯胺耐藥至關(guān)重要。從機制上講，巨噬細(xì)胞通過細(xì)胞因子激活素 A 驅(qū)動耐藥性，從而在 PC 細(xì)胞中誘導(dǎo)纖連蛋白 （FN1）-整合素 α 5 （ITGA5）-酪氨酸激酶 Src （SRC） 信號級聯(lián)反應(yīng)。這種新機制得到了患者轉(zhuǎn)錄組學(xué)數(shù)據(jù)集的生物信息學(xué)分析的強烈支持。此外，使用新型特異性抑制劑的巨噬細(xì)胞耗竭或 SRC 抑制顯著抑制了耐藥生長?？傊覀兊难芯拷Y(jié)果闡明了巨噬細(xì)胞誘導(dǎo)的轉(zhuǎn)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(zhì)體助力前列腺癌骨轉(zhuǎn)移模型巨噬細(xì)胞研究，Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes見刊于JEM：
Liposoma巨噬細(xì)胞清除劑Clodronate Liposomes氯膦酸二鈉脂質(zhì)體的材料和方法：
JEM期刊巨噬細(xì)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.
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