Gonçalves Renata de Castro, Freire Paula Paccielli, Coletti Dario, Seelaender Marilia
Cancer Metabolism Research Group, Department of Surgery, LIM26-HC, Faculdade de Medicina, and Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Front Oncol. 2021 Feb 2;10:617109. doi: 10.3389/fonc.2020.617109. eCollection 2020.
Cachexia is a syndrome that affects the entire organism and presents a variable plethora of symptoms in patients, always associated with continuous and involuntary degradation of skeletal muscle mass and function loss. In cancer, this syndrome occurs in 50% of all patients, while prevalence increases to 80% as the disease worsens, reducing quality of life, treatment tolerance, therapeutic response, and survival. Both chronic systemic inflammation and immunosuppression, paradoxically, correspond to important features in cachexia patients. Systemic inflammation in cachexia is fueled by the interaction between tumor and peripheral tissues with significant involvement of infiltrating immune cells, both in the peripheral tissues and in the tumor itself. Autophagy, as a process of regulating cellular metabolism and homeostasis, can interfere with the metabolic profile in the tumor microenvironment. Under a scenario of balanced autophagy in the tumor microenvironment, the infiltrating immune cells control cytokine production and secretion. On the other hand, when autophagy is unbalanced or dysfunctional within the tumor microenvironment, there is an impairment in the regulation of immune cell's inflammatory phenotype. The inflammatory phenotype upregulates metabolic consumption and cytokine production, not only in the tumor microenvironment but also in other tissues and organs of the host. We propose that cachexia-related chronic inflammation can be, at least, partly associated with the failure of autophagic processes in tumor cells. Autophagy endangers tumor cell viability by producing immunogenic tumor antigens, thus eliciting the immune response necessary to counteract tumor progression, while preventing the establishment of inflammation, a hallmark of cachexia. Comprehensive understanding of this complex functional dichotomy may enhance cancer treatment response and prevent/mitigate cancer cachexia. This review summarizes the recent available literature regarding the role of autophagy within the tumor microenvironment and the consequences eliciting the development of cancer cachexia.
恶病质是一种影响整个机体的综合征，患者会出现各种各样的症状，且总是伴随着骨骼肌质量的持续非自愿性下降和功能丧失。在癌症患者中，50%会出现这种综合征，而随着病情恶化，患病率会升至80%，这会降低生活质量、治疗耐受性、治疗反应以及生存率。矛盾的是，慢性全身炎症和免疫抑制是恶病质患者的重要特征。恶病质中的全身炎症是由肿瘤与外周组织之间的相互作用引发的，外周组织和肿瘤本身中浸润的免疫细胞也大量参与其中。自噬作为调节细胞代谢和内环境稳定的过程，会干扰肿瘤微环境中的代谢特征。在肿瘤微环境中自噬平衡的情况下，浸润的免疫细胞会控制细胞因子的产生和分泌。另一方面，当肿瘤微环境中的自噬失衡或功能失调时，免疫细胞炎症表型的调节就会受损。炎症表型不仅会上调肿瘤微环境中的代谢消耗和细胞因子产生，还会上调宿主其他组织和器官中的代谢消耗和细胞因子产生。我们认为，恶病质相关的慢性炎症至少部分与肿瘤细胞自噬过程的失败有关。自噬通过产生免疫原性肿瘤抗原来危及肿瘤细胞的生存能力，从而引发对抗肿瘤进展所需的免疫反应，同时防止炎症的发生，而炎症是恶病质的一个标志。全面理解这种复杂的功能二分法可能会增强癌症治疗反应，并预防/减轻癌症恶病质。本综述总结了近期关于自噬在肿瘤微环境中的作用以及引发癌症恶病质发展的后果的现有文献。
