Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
J Hematol Oncol. 2021 May 14;14(1):79. doi: 10.1186/s13045-021-01087-1.
Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.
长期以来，溶酶体一直被认为是消化细胞器，但现在它已成为负责降解、营养感应和免疫的多面中心。越来越多的证据表明，溶酶体相关机制在病理过程中也起着作用。在这篇综述中，我们讨论了溶酶体的生理功能，更重要的是，溶酶体的动态平衡如何在几种疾病中被打破，包括动脉粥样硬化、神经退行性疾病、自身免疫性疾病、胰腺炎、溶酶体贮积症和恶性肿瘤。在动脉粥样硬化和戈谢病中，溶酶体功能障碍改变了巨噬细胞中细胞因子的分泌，部分是通过炎性小体的激活。在神经退行性疾病中，缺陷的自噬促进了有毒蛋白和功能失调细胞器的积累，导致神经元死亡。溶酶体功能障碍已在胰腺炎的病理学中得到证实。在自身免疫性疾病中，异常的自噬激活或抑制已被揭示。在肿瘤微环境中，肿瘤细胞的恶性表型，包括肿瘤发生、生长调控、侵袭、耐药和放疗抵抗，以及肿瘤相关巨噬细胞、成纤维细胞、树突状细胞和 T 细胞的行为，也受溶酶体介导。基于这些发现，一系列针对溶酶体蛋白和过程的治疗方法已从实验室发展到临床。总之，目前的研究证实，溶酶体是理解动脉粥样硬化、神经退行性疾病、自身免疫性疾病、胰腺炎、溶酶体贮积症和恶性肿瘤的病理学以及开发新的治疗策略的关键细胞器。
