The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan; The Program for Translational Medicine, Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.
Toxicol Appl Pharmacol. 2020 Aug 15;401:115109. doi: 10.1016/j.taap.2020.115109. Epub 2020 Jun 13.
Bladder cancer (BCa) is the fourth leading cause of cancer deaths worldwide due to its aggressiveness and resistance against therapies. Intricate interactions between cancer cells and the tumor microenvironment (TME) are essential for both disease progression and regression. Thus, interrupting molecular communications within the TME could potentially provide improved therapeutic efficacies. M2-polarized tumor-associated macrophages (M2 TAMs) were shown to contribute to BCa progression and drug resistance. We attempted to provide evidence for ovatodiolide (OV) as a potential therapeutic agent that targets both TME and BCa cells. First, tumor-suppressing functions of OV were determined by cell viability, colony, and tumor-sphere formation assays using a coculture system composed of M2 TAMs/BCa cells. Subsequently, we demonstrated that extracellular vesicles (EVs) isolated from M2 TAMs containing oncomiR-21 and mRNAs, including Akt, STAT3, mTOR, and β-catenin, promoted cisplatin (CDDP) resistance, migration, and tumor-sphere generation in BCa cells, through increasing CDK6, mTOR, STAT3, and β-catenin expression. OV treatment also prevented M2 polarization and reduced EV cargos from M2 TAMs. Finally, in vivo data demonstrated that OV treatment overcame CDDP resistance. OV only and the OV + CDDP combination both resulted in significant reductions in mTOR, β-catenin, CDK6, and miR-21 expression in tumor samples and EVs isolated from serum. Collectively, we demonstrated that M2 TAMs induced malignant properties in BCa cells, in part via oncogenic EVs. OV treatment prevented M2 TAM polarization, reduced EV cargos derived from M2 TAMs, and suppressed β-catenin/mTOR/CDK6 signaling. These findings provide preclinical evidence for OV as a single or adjuvant agent for treating drug-resistant BCa.
膀胱癌 (BCa) 是全球第四大癌症死亡原因，其原因是其侵袭性和对治疗的耐药性。癌细胞与肿瘤微环境 (TME) 之间的复杂相互作用对疾病的进展和消退都至关重要。因此，中断 TME 内的分子通讯可能会提供改善的治疗效果。已表明 M2 极化的肿瘤相关巨噬细胞 (M2 TAMs) 有助于 BCa 的进展和耐药性。我们试图提供证据证明卵形菌萜内酯 (OV) 是一种潜在的治疗剂，可同时针对 TME 和 BCa 细胞。首先，通过使用由 M2 TAMs/BCa 细胞组成的共培养系统进行细胞活力、集落和肿瘤球体形成测定，确定了 OV 的肿瘤抑制功能。随后，我们证明了从含有致癌 miRNA-21 和包括 Akt、STAT3、mTOR 和 β-catenin 在内的 mRNAs 的 M2 TAMs 分离的细胞外囊泡 (EVs) 通过增加 CDK6、mTOR、STAT3 和 β-catenin 表达，促进了 BCa 细胞对顺铂 (CDDP) 的耐药性、迁移和肿瘤球体生成。OV 处理还可防止 M2 极化并减少 M2 TAMs 中的 EV cargos。最后，体内数据表明 OV 治疗克服了 CDDP 耐药性。OV 单独和 OV+CDDP 联合治疗均导致肿瘤样本和从血清中分离的 EV 中 mTOR、β-catenin、CDK6 和 miR-21 的表达显著降低。总之，我们证明 M2 TAMs 通过致癌性 EVs 诱导 BCa 细胞产生恶性特性。OV 处理可防止 M2 TAM 极化，减少 M2 TAMs 衍生的 EV cargos，并抑制 β-catenin/mTOR/CDK6 信号通路。这些发现为 OV 作为治疗耐药性 BCa 的单一或辅助药物提供了临床前证据。
