Mahgoub Eglal, Taneera Jalal, Sulaiman Nabil, Saber-Ayad Maha
College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.
Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
Front Med (Lausanne). 2022 Sep 7;9:959348. doi: 10.3389/fmed.2022.959348. eCollection 2022.
Colorectal cancer (CRC) is considered as a global major cause of cancer death. Surgical resection is the main line of treatment; however, chemo-, radiotherapy and other adjuvant agents are crucial to achieve good outcomes. The tumor microenvironment (TME) is a well-recognized key player in CRC progression, yet the processes linking the cancer cells to its TME are not fully delineated. Autophagy is one of such processes, with a controversial role in the pathogenesis of CRC, with its intricate links to many pathological factors and processes. Autophagy may apparently play conflicting roles in carcinogenesis, but the precise mechanisms determining the overall direction of the process seem to depend on the context. Additionally, it has been established that autophagy has a remarkable effect on the endothelial cells in the TME, the key substrate for angiogenesis that supports tumor metastasis. Favorable response to immunotherapy occurs only in a specific subpopulation of CRC patients, namely the microsatellite instability-high (MSI-H). In view of such limitations of immunotherapy in CRC, modulation of autophagy represents a potential adjuvant strategy to enhance the effect of those relatively safe agents on wider CRC molecular subtypes. In this review, we discussed the molecular control of autophagy in CRC and how autophagy affects different processes and mechanisms that shape the TME. We explored how autophagy contributes to CRC initiation and progression, and how it interacts with tumor immunity, hypoxia, and oxidative stress. The crosstalk between autophagy and the TME in CRC was extensively dissected. Finally, we reported the clinical efforts and challenges in combining autophagy modulators with various cancer-targeted agents to improve CRC patients' survival and restrain cancer growth.
结直肠癌（CRC）被认为是全球癌症死亡的主要原因之一。手术切除是主要的治疗方法；然而，化疗、放疗和其他辅助药物对于取得良好疗效至关重要。肿瘤微环境（TME）是CRC进展中一个公认的关键因素，但其将癌细胞与其TME联系起来的过程尚未完全阐明。自噬就是这样一种过程，在CRC发病机制中具有争议性作用，它与许多病理因素和过程有着复杂的联系。自噬在致癌过程中可能明显发挥相互矛盾的作用，但决定该过程总体方向的精确机制似乎取决于具体情况。此外，已经证实自噬对TME中的内皮细胞有显著影响，而内皮细胞是支持肿瘤转移的血管生成的关键底物。只有在特定亚群的CRC患者中，即微卫星高度不稳定（MSI-H）患者，才会对免疫疗法产生良好反应。鉴于CRC免疫疗法存在这些局限性，调节自噬代表了一种潜在的辅助策略，以增强这些相对安全的药物对更广泛的CRC分子亚型的疗效。在这篇综述中，我们讨论了CRC中自噬的分子调控，以及自噬如何影响塑造TME的不同过程和机制。我们探讨了自噬如何促进CRC的发生和进展，以及它如何与肿瘤免疫、缺氧和氧化应激相互作用。广泛剖析了CRC中自噬与TME之间的相互作用。最后，我们报告了将自噬调节剂与各种癌症靶向药物联合使用以提高CRC患者生存率和抑制癌症生长的临床努力和挑战。
