The function of macroautophagy/autophagy during tumor initiation or in established tumors can be highly distinct and context-dependent. To investigate the role of autophagy in gliomagenesis, we utilized a KRAS-driven glioblastoma mouse model in which autophagy is specifically disrupted via RNAi against Atg7, Atg13 or Ulk1. Inhibition of autophagy strongly reduced glioblastoma development, demonstrating its critical role in promoting tumor formation. Further supporting this finding is the observation that tumors originating from Atg7-shRNA injections escaped the knockdown effect and thereby still underwent functional autophagy. In vitro, autophagy inhibition suppressed the capacity of KRAS-expressing glial cells to form oncogenic colonies or to survive low serum conditions. Molecular analyses revealed that autophagy-inhibited glial cells were unable to maintain active growth signaling under growth-restrictive conditions and were prone to undergo senescence. Overall, these results demonstrate that a...

https://www.tandfonline.com/doi/pdf/10.1080/15548627.2016.1190053

Suppression of autophagy impedes glioblastoma development and induces senescence

Radiation is a critical pillar in cancer therapeutics, exerting its anti-tumor DNA-damaging effects through various direct and indirect mechanisms. Radiation has served as an effective mode of treatment for a number of cancer types, providing both curative and palliative treatment; however, resistance to therapy persists as a fundamental limitation. While cancer cell death is the ideal outcome of any anti-tumor treatment, radiation induces several responses, including apoptotic cell death, mitotic catastrophe, autophagy and senescence, where autophagy and senescence may promote cell survival. In most cases, autophagy, a conventionally cytoprotective mechanism, is a "first" responder to damage incurred from chemotherapy and radiation treatment. The paradigm developed on the premise that autophagy is cytoprotective in nature has provided the rationale for current clinical trials designed with the goal of radiosensitizing cancer cells through the use of autophagy inhibitors; however, these have failed to produce consistent results. Delving further into pre-clinical studies, autophagy has actually been shown to take diverse, sometimes opposing, forms, such as acting in a cytotoxic or nonprotective fashion, which may be partially responsible for the inconsistency of clinical outcomes. Furthermore, autophagy can have both pro- and anti-tumorigenic effects, while also having an important immune modulatory function. Senescence often occurs in tandem with autophagy, which is also the case with radiation. Radiation-induced senescence is frequently followed by a phase of proliferative recovery in a subset of cells and has been proposed as a tumor dormancy model, which can contribute to resistance to therapy and possibly also disease recurrence. Senescence induction is often accompanied by a unique secretory phenotype that can either promote or suppress immune functions, depending on the expression profile of cytokines and chemokines. Novel therapeutics selectively cytotoxic to senescent cells (senolytics) may prove to prolong remission by delaying disease recurrence in patients. Accurate assessment of primary responses to radiation may provide potential targets that can be manipulated for therapeutic benefit to sensitize cancer cells to radiotherapy, while sparing normal tissue.

https://bioone.org/journals/radiation-research/volume-194/issue-2/RADE-20-00009/The-Roles-of-Autophagy-and-Senescence-in-the-Tumor-Cell/10.1667/RADE-20-00009.pdf

The Roles of Autophagy and Senescence in the Tumor Cell Response to Radiation.

Therapy-Induced Senescence (TIS) is an established response to anticancer therapy in a variety of cancer models. Ample evidence has characterized the triggers, hallmarks, and functional outcomes of TIS in preclinical studies; however, limited evidence delineates TIS in clinical cancer (human tumor samples). We examined the literature that investigated the induction of TIS in samples derived from human cancers and highlighted the major findings that suggested that TIS represents a main constituent of tumor biology. The most frequently utilized approach to identify TIS in human cancers was to investigate the protein expression of senescence-associated markers (such as cyclins, cyclin-dependent kinase inhibitors, Ki67, DNA damage repair response markers, DEC1, and DcR1) via immunohistochemical techniques using formalin-fixed paraffin-embedded (FFPE) tissue samples and/or testing the upregulation of Senescence-Associated β-galactosidase (SA-β-gal) in frozen sections of unfixed tumor samples. Collectively, and in studies where the extent of TIS was determined, TIS was detected in 31-66% of tumors exposed to various forms of chemotherapy. Moreover, TIS was not only limited to both malignant and non-malignant components of tumoral tissue but was also identified in samples of normal (non-transformed) tissue upon chemo- or radiotherapy exposure. Nevertheless, the available evidence continues to be limited and requires a more rigorous assessment of in vivo senescence based on novel approaches and more reliable molecular signatures. The accurate assessment of TIS will be beneficial for determining its relevant contribution to the overall outcome of cancer therapy and the potential translatability of senotherapeutics. 

Therapy-induced senescence as a component of tumor biology: Evidence from clinical cancer.

Mechanical stress-induced autophagic response: A cancer-enabling characteristic?

To understand the mechanism underlying autophagy in regulating dendritic cells during rat liver regeneration, we used the method of percoll density gradient centrifugation combined with immunomagnetic bead to isolate dendritic cells, the Rat Genome 230 20 Array to determine the expression changes of autophagy-related genes, and Ingenuity Pathway Analysis 90 (IPA) to determine the autophagy activities The results indicated that LC3, BECN1, ATG7 and SQSTM1 genes had significant expression changes during rat liver regeneration There were 593 genes related to autophagy, among which 210 genes were identified as significant We also showed that the activity of autophagy was enhanced in the priming phase and teminal phase of liver regeneration, weakened in the proliferative stage by comparative analysis method of IPA The autophagy-related physiological activities mainly included RNA expression, RNA transcription, cell differentiation and proliferation, involving in PPARα/RXRα activation, acute phase response signaling, TREM1 signaling, IL-6 signaling, IL-8 signaling and IL-1 signaling, whose activities were increased or decreased in liver regeneration Cluster analysis found that P53 and AMPK signaling participated in the regulation of dendritic cells autophagy, with AMPK signaling in the priming phase of liver regeneration, and both signaling pathways in the terminal phase We conclude that dendritic cells autophagy played an important role in initiation of the immune response in priming phase and depletion of dendritic cells in late phase during rat liver regeneration

Regulation of autophagy on dendritic cells during rat liver regeneration by IPA

macroautophagy 的角色(此后 autophagy ) 在癌症，到临床的干预的生物学和反应是复杂的。autophagy 是在许多肿瘤背景的 dysregulated，是清楚的，在肿瘤开始和前进期间，并且响应治疗。然而，在控制房间行为的 autophagy 的多种的机械学的角色使在一个给定的肿瘤背景预言困难 autophagy 的角色，并且，由扩展，指向 autophagy 的治疗学的结果，力量。在这评论，我们在在癌症支持 pro-tumorigenic 和 anti-tumorigenic 和 autophagy 的治疗学的角色的文学总结证据。这概述在滋养的管理，房间死亡，房间老朽， proteotoxic 应力的规定和细胞的动态平衡包含 autophagy 的角色，在在新陈代谢的变化的肿瘤主人相互作用和参予的规定。在可能的地方，我们也试着理解，为 autophagy 的这些角色的机械学的底。我们明确地阐述在在 vivo.We 使这些问题清楚些的癌症的模型也考虑 autophagy 蛋白质的任何东西或上述所有函数怎么可能是可指向的由的遗传上设计的老鼠的新兴的角色现存或 pharmacologic 代理人的未来类。我们由简短在细胞的过程为关键 autophagy 蛋白质的子集探索不在经典中的角色得出结论，并且这些怎么可能在癌症之上影响。

Autophagy in cancer biology and therapy

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Autophagy in cancer biology and therapy