Department of Urology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Int J Biol Sci. 2023 Jul 31;19(12):3951-3969. doi: 10.7150/ijbs.85209. eCollection 2023.
Numerous studies have substantiated the association between aging and the progression of malignant tumors in humans, notably prostate cancer (PCa). Nevertheless, to the best of our knowledge, no studies have comprehensively elucidated the intricate characteristics of the aging microenvironment (AME) in PCa. AME regulatory patterns were determined using the NMF algorithm. Then an ageing microenvironment index (AMI) was constructed, with excellent prognostic and immunotherapy prediction ability, and its' clinical relevance was surveyed through spatial transcriptomics. Further, the drug response was analysed using the Genomics of Drug Sensitivity in Cancer (GDSC), the Connectivity Map (CMap) and CellMiner database for patients with PCa. Finally, the AME was studied using in vitro and vivo experiments. Three different AME regulatory patterns were identified across 813 PCa patients, associated with distinct clinical prognosis and physiological pathways. Based on the AMI, patients with PCa were divided into the high-score and low-score subsets. Higher AMI score was significantly infiltrated with more immune cells, higher rate of biochemical recurrence (BCR) and worse response to immunotherapy, antiandrogen therapy and chemotherapy in PCa. In addition, we found that the combination of bicalutamide and embelin was capable of suppressing tumor growth of PCa. Besides, as the main components of AMI, and act as oncogenes and were verified via in vivo and in vitro experiments. AME regulation is significantly associated with the diversity and complexity of TME. Quantitative evaluation of the AME regulatory patterns may provide promising novel molecular markers for individualised therapy in PCa.
大量研究证实了衰老与人类恶性肿瘤进展之间的关联，尤其是前列腺癌（PCa）。然而，据我们所知，尚无研究全面阐明 PCa 衰老微环境（AME）的复杂特征。AME 调节模式使用 NMF 算法确定。然后构建了一个衰老微环境指数（AMI），具有出色的预后和免疫治疗预测能力，并通过空间转录组学调查其临床相关性。此外，使用癌症药物敏感性基因组学（GDSC）、连接图谱（CMap）和前列腺癌患者的 CellMiner 数据库分析药物反应。最后，通过体外和体内实验研究 AME。在 813 名 PCa 患者中鉴定出三种不同的 AME 调节模式，与不同的临床预后和生理途径相关。基于 AMI，将 PCa 患者分为高分和低分亚组。较高的 AMI 评分与更多的免疫细胞浸润、更高的生化复发（BCR）率以及对 PCa 的免疫治疗、抗雄激素治疗和化疗的反应较差显著相关。此外，我们发现比卡鲁胺和榄香烯的联合使用能够抑制 PCa 的肿瘤生长。此外，作为 AMI 的主要成分，和在体内和体外实验中被验证为癌基因。AME 调节与 TME 的多样性和复杂性密切相关。AME 调节模式的定量评估可能为 PCa 的个体化治疗提供有前途的新型分子标志物。
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