Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
Medical University of Astana, Astana, Kazakhstan.
Med Oncol. 2023 Jul 11;40(8):236. doi: 10.1007/s12032-023-02078-7.
Bladder cancer is a therapeutically challenging disease and wealth of knowledge has enabled researchers to develop a clear understanding of mechanisms which underlie carcinogenesis and metastasis. Excitingly, research over decades has unveiled wide-ranging mechanisms which serve as central engine in progression of bladder cancer. Loss of apoptosis, drug resistance, and pro-survival signaling are some of the highly studied cellular mechanisms. Therefore, restoration of apoptosis in resistant cancers is a valuable and attractive strategy. Discovery of TRAIL-mediated signaling cascade is an intriguing facet of molecular oncology. In this review, we have provided an overview of the translational and foundational advancements in dissecting the genomic and proteomic cartography of TRAIL signaling exclusively in the context of bladder cancer. We have also summarized how different natural products sensitized drug-resistant bladder cancer cells to TRAIL-mediated apoptosis. Interestingly, different death receptors that activate agonistic antibodies have been tested in various phases of clinical trials against different cancers. Certain clues of scientific evidence have provided encouraging results about efficacy of these agonistic antibodies (lexatumumab and mapatumumab) against bladder cancer cell lines. Therefore, multipronged approaches consisting of natural products, chemotherapeutics, and agonistic antibodies will realistically and mechanistically provide proof-of-concept for the translational potential of these combinatorial strategies in well-designed clinical trials.
膀胱癌是一种具有挑战性的治疗疾病，丰富的知识使研究人员能够清楚地了解致癌和转移的机制。令人兴奋的是，几十年来的研究揭示了广泛的机制，这些机制是膀胱癌进展的核心引擎。细胞凋亡的丧失、耐药性和存活信号的产生是一些研究较多的细胞机制。因此，在耐药性癌症中恢复细胞凋亡是一种有价值且有吸引力的策略。TRAIL 介导的信号级联的发现是分子肿瘤学的一个有趣方面。在这篇综述中，我们概述了在专门针对膀胱癌的情况下，对 TRAIL 信号的基因组和蛋白质组图谱进行解析的转化和基础进展。我们还总结了不同的天然产物如何使耐药性膀胱癌细胞对 TRAIL 介导的细胞凋亡敏感。有趣的是，不同的死亡受体激活激动性抗体已在不同的临床试验阶段针对不同的癌症进行了测试。关于这些激动性抗体（lexatumumab 和 mapatumumab）对膀胱癌细胞系的疗效，一些科学证据提供了令人鼓舞的结果。因此，由天然产物、化疗药物和激动性抗体组成的多管齐下的方法将为这些组合策略在精心设计的临床试验中的转化潜力提供实际和机制上的证据。
