自噬与肿瘤

自噬在维持细胞的正常代谢及生存过程中有着重要作用,其在肿瘤的发生机制中也不容忽视,自噬的过程源于自噬小体的形成,包括了诱导、成核、延长、形成完整隔离膜4个步骤。本文就自噬的分子机制、检测方法及其与肿瘤方面的研究进展加以综述。     

线粒体自噬的信号通路及其在肿瘤中的研究进展

线粒体自噬是真核生物细胞中广泛存在的清除功能失调或者多余线粒体的一种高度保守的细胞进程,能很好地调整线粒体数目并维持细胞能量代谢的稳定。该过程较复杂,多种信号通路参与其中来诱导或抑制线粒体自噬,从而以多重角度监测它的正常进行。而在恶性肿瘤中,线粒体自噬涉及到癌细胞的异常活化与增殖,提示它既可在癌细胞内发挥促癌效应,又可在正常细胞中发挥抑癌效应,二者之间的平衡可以决定肿瘤的进展或凋亡。从这个角度可以形成一条抗癌治疗新思路,既可抑制癌细胞中的线粒体自噬发挥抑癌效应,又可增强正常细胞中的线粒体自噬,清除损伤线粒体,维持线粒体基因组稳定与正常功能,从而发挥抑癌作用。本综述主要探讨线粒体自噬中涉及的多种信号通路及发挥关键作用的分子,并阐述线粒体自噬与恶性肿瘤的关系。     

自噬与肿瘤转移的相关性研究

自噬是一种在正常细胞和肿瘤细胞中普遍存在的生命现象。肿瘤细胞通过转移定植到远隔器官,必须适应严峻恶劣的微环境。在这一系列转移事件中,自噬发挥了双重作用。研究证明自噬能抑制原发性肿瘤的形成,但关于自噬如何影响肿瘤转移尚不清楚,本文将对自噬的概念及生物学特性、肿瘤转移的基本过程、自噬在肿瘤转移过程中的作用机制以及自噬在肿瘤治疗中的应用做一综述。     

细胞自噬及其在乳腺癌中的研究进展

自噬是一种在生物进化过程中发生的细胞分解代谢过程,细胞内膜结构、蛋白质复合物和溶酶体形成自噬溶酶体用于降解和更新细胞成分.自噬是为细胞内稳态以及适应压力而发生的生理性调节,自噬机制发生改变会导致不同的病理条件.在肿瘤中自噬是复杂的,并且具有双面效应.在多种乳腺癌类型中,自噬有希望成为一种新的靶向治疗策略.本文旨在总结在肿瘤转移中自噬参与调节的主要分子机制,以及在肿瘤治疗中自噬所起的作用.     

自噬在肿瘤发生发展及治疗中的作用

自噬是真核细胞生长分化、功能发挥及死亡的重要调控机制,自噬异常与肿瘤等多种人类疾病的发生发展有关。在分子水平,自噬与细胞的凋亡、增殖信号相互作用,共同影响肿瘤细胞的存活与死亡。由于自噬主要起维持细胞生存的功能,抑制自噬就成为辅助肿瘤治疗的一个新方向;然而,抑制自噬后的肿瘤细胞又具有逃避死亡的潜在危险,而限制了这一疗法的应用。自噬与肿瘤的复杂关系正日益受到关注,揭示其分子机制必将对肿瘤治疗产生深刻的影响。     

自噬与肝细胞癌关系的研究进展

自噬是细胞在溶酶体的参与下降解细胞物质或结构的过程。人类许多疾病与自噬异常有关, 为人类癌症中的病理生理学提供了新的线索。但是自噬在正常肝脏生理和肝脏疾病发病过程中的作用有待进一步阐明。文章综述了目前已知的自噬在肝细胞癌发生、发展中的作用及分子机制。     

细胞自噬在肝癌发生发展中的作用

细胞自噬是细胞内高度保守的细胞自我消化和分解代谢过程,是维持细胞内稳态的重要机制之一。在肝癌发生发展的不同阶段,细胞自噬起着不同作用。在肝癌的起始阶段,经常存在自噬缺陷,这也可说明细胞自噬的正常运转可抑制肝癌的发生;但是在肝癌的发展过程中,随着肿瘤微环境的变化,肝癌细胞也会利用自噬来保护自己。故自噬所扮演的角色也在改变,起着保护肝癌细胞的作用。另外,自噬与肝癌细胞的转移及耐药也密切相关。     

自噬与肿瘤

近期研究发现自噬不仅对细胞内自我平衡调节起着重要作用,而且在肿瘤的发生发展中起着双刃剑的作用。研究自噬的分子机制以及自噬与肿瘤的关系对肿瘤防治有重大意义。     

自体吞噬在肿瘤发展中的作用及其与肿瘤治疗

自体吞噬是一种在正常细胞和病态细胞中普遍存在的生理机制,对于维持细胞内蛋白质平衡,清除细胞内受损细胞器维持内环境稳定起关键作用.自噬在肿瘤不同发展阶段具有促进或抑制肿瘤两方面的作用,通过药物改变肿瘤细胞的自噬程度对于治疗肿瘤有着潜在的应用前景.     

自噬与肿瘤

近期研究发现自噬不仅对细胞内自我平衡调节起着重要作用,而且在肿瘤的发生发展中起着双刃剑的作用.研究自噬的分子机制以及自噬与肿瘤的关系对肿瘤防治有重大意义.     

Autophagy facilitates the release of immunogenic signals following chemotherapy in 3D models of mesothelioma

We have previously shown that nearly half of mesothelioma patients have tumors with low autophagy and that these patients have a significantly worse outcome than those with high autophagy. We hypothesized that autophagy may be beneficial by facilitating immunogenic cell death (ICD) of tumor cells following chemotherapy. An important hallmark of ICD is that death of tumor cells is preceded or accompanied by the release of damage‐associated molecular pattern molecules (DAMPs), which then can stimulate an antitumor immune response. Therefore, we measured how autophagy affected the release of three major DAMPs: high mobility group box 1 (HMGB1), ATP, and calreticulin following chemotherapy. We found that autophagy in three‐dimensional (3D) models with low autophagy at baseline could be upregulated with the cell‐permeant Tat‐BECN1 peptide and confirmed that autophagy in 3D models with high autophagy at baseline could be inhibited with MRT 68921 or ATG7 RNAi, as we have previously shown. In in vitro 3D spheroids, we found that, when autophagy was high or upregulated, DAMPs were released following chemotherapy; however, when autophagy was low or inhibited, DAMPs release was significantly impaired. Similarly, in ex vivo tumors, when autophagy was high or upregulated, HMGB1 was released following chemotherapy but, when autophagy was low, HMGB1 release was not seen. We conclude that autophagy can be upregulated in at least some tumors with low autophagy and that upregulation of autophagy can restore the release of DAMPs following chemotherapy. Autophagy may be necessary for ICD in this tumor.     

Autophagy and multidrug resistance in cancer

Multidrug resistance (MDR) occurs frequently after long-term chemotherapy,resulting in refractory cancer and tumor recurrence.Therefore,combatting MDR is an important issue.Autophagy,a self-degradative system,universally arises during the treatment of sensitive and MDR cancer.Autophagy can be a double-edged sword for MDR tumors:it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive.Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells,facilitating MDR reversal.Therefore,research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important.We summarize advanced studies of autophagy in MDR tumors,including the variable role of autophagy in MDR cancer cells.     

自噬在肿瘤血管形成及放射敏感性中作用的研究进展

自噬是细胞对环境变化的有效反应,在机体的生理和病理过程中都能观察到。自噬在肿瘤的发生发展及治疗的过程中发挥着重要的作用。肿瘤血管形成是指肿瘤细胞诱导的微血管生成及肿瘤中血液循环建立,是肿瘤发生、发展及侵袭与转移的重要条件。自噬和肿瘤血管形成作为肿瘤进展的重要影响因素,两者之间存在着复杂的联系。放射治疗是肿瘤的治疗方案之一,放疗效果受多种因素影响,有研究表明自噬在肿瘤的放射敏感性中起着极其重要的作用。现就自噬在肿瘤血管形成及放射敏感性中作用的研究进展进行更深入的探讨,以期为肿瘤的治疗提供新的研究方向。     

Role of autophagy in gastric carcinogenesis

Gastric cancer represents a common and highly fatal malignancy, and thus a pathophysiology-based reconsideration is necessary, given the absence of efficient therapeutic regimens. In this regard, emerging data reveal a significant role of autophagy in gastric oncogenesis, progression, metastasis and chemoresistance. Although autophagy comprises a normal primordial process, ensuring cellular homeostasis under energy depletion and stress conditions, alterations at any stage of the complex regulatory system could stimulate a tumorigenic and promoting cascade. Among others, Helicobacter pylori infection induces a variety of signaling molecules modifying autophagy, during acute infection or after chronic autophagy degeneration. Subsequently, defective autophagy allows malignant transformation and upon cancer establishment, an overactive autophagy is stimulated. This overexpressed autophagy provides energy supplies and resistance mechanisms to gastric cancer cells against hosts defenses and anticancer treatment. This review interprets the implicated autophagic pathways in normal cells and in gastric cancer to illuminate the potential preventive, therapeutic and prognostic benefits of understanding and intervening autophagy.     

Inhibition of autophagy at a late stage enhances imatinib‐induced cytotoxicity in human malignant glioma cells

Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Imatinib mesylate, a tyrosine kinase inhibitor, is effective in the therapy of tumors including leukemias but not as a monotherapy for malignant glioma. Recently, it is thought that the adequate modulation of autophagy can enhance efficacy of anticancer therapy. The outcome of autophagy manipulation, however, seems to depend on the autophagy initiator, the combined stimuli, the extent of cellular damage and the type of cells, and it is not yet fully understood how we should modulate autophagy to augment efficacy of each anticancer therapy. In this study, we examined the effect of imatinib with or without different types of autophagy inhibitors on human malignant glioma cells. Imatinib inhibited the viability of U87‐MG and U373‐MG cells in a dose dependent manner and caused nonapoptotic autophagic cell death. Suppression of imatinib‐induced autophagy by 3‐methyladenine or small interfering RNA against Atg5, which inhibit autophagy at an early stage, attenuated the imatinib‐induced cytotoxicity. In contrast, inhibition of autophagy at a late stage by bafilomycin A1 or RTA 203 enhanced imatinib‐induced cytotoxicity through the induction of apoptosis following mitochondrial disruption. Our findings suggest that therapeutic efficiency of imatinib for malignant glioma may be augmented by inhibition of autophagy at a late stage, and that appropriate modulation of autophagy may sensitize tumor cells to anticancer therapy. © 2008 Wiley‐Liss, Inc.     

Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo

Autophagy is of increasing interest as a target for cancer therapy. We find that leucine deprivation causes the caspase-dependent apoptotic death of melanoma cells because it fails to appropriately activate autophagy. Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. In an in vivo tumor xenograft model, the combination of a leucine-free diet and an autophagy inhibitor synergistically suppresses the growth of human melanoma tumors and triggers widespread apoptosis of the cancer cells. Together, our study represents proof of principle that anticancer effects can be obtained with a combination of autophagy inhibition and strategies to deprive tumors of leucine.     

Cell-mediated autophagy promotes cancer cell survival

Immune effector cells integrate signals that define the nature and magnitude of the subsequent response. Experimental measures for immune cell-mediated lysis of tumors or virally infected targets rely on average responses of permeability or apoptotic changes within a population of targets. Here, we examined individual target cells following interaction with lymphoid effectors. We found that human peripheral blood lymphocytes not only provide lytic signals but also promote autophagy in the remaining cells. At high effector-to-target ratios, autophagy was induced in several human tumors, as assessed by induction of LC3 puncta and diminished p62. Natural killer cells are a primary mediator of this process. In addition, target cell autophagy was enhanced by provision of interleukin (IL)-2, whereas IL-10 attenuated this effect, and cell-to-cell contact strongly enhanced lymphocyte-mediated autophagy. Although IFN-γ can induce autophagy in target cells, IFN-α acted directly on the targets or in concert with lymphocytes to diminish target autophagy in some cell types. Importantly, cell-mediated autophagy promoted resistance from treatment modalities designed to eradicate tumor cells. Our findings therefore show that the lymphocyte-induced cell-mediated autophagy promotes cancer cell survival and may represent an important target for development of novel therapies.     

EGFR overexpressing cells and tumors are dependent on autophagy for growth and survival

Background and purpose

The epidermal growth factor receptor (EGFR) is overexpressed, amplified or mutated in various human epithelial tumors, and is associated with tumor aggressiveness and therapy resistance. Autophagy activation provides a survival advantage for cells in the tumor microenvironment. In the current study, we assessed the potential of autophagy inhibition (using chloroquine (CQ)) in treatment of EGFR expressing tumors.

Material and methods

Quantitative PCR, immunohistochemistry, clonogenic survival, proliferation assays and in vivo tumor growth were used to assess this potential.

Results

We show that EGFR overexpressing xenografts are sensitive to CQ treatment and are sensitized to irradiation by autophagy inhibition. In HNSSC xenografts, a correlation between EGFR and expression of the autophagy marker LC3b is observed, suggesting a role for autophagy in EGFR expressing tumors. This observation was substantiated in cell lines, showing high EGFR expressing cells to be more sensitive to CQ addition as reflected by decreased proliferation and survival. Surprisingly high EGFR expressing cells display a lower autophagic flux.

Conclusions

The EGFR high expressing cells and tumors investigated in this study are highly dependent on autophagy for growth and survival. Inhibition of autophagy may therefore provide a novel treatment opportunity for EGFR overexpressing tumors.     

Autophagy in colorectal cancer: An important switch from physiology to pathology

Colorectal cancer (CRC) remains a leading cause of cancer death in both men and women worldwide. Among the factors and mechanisms that are involved in the multifactorial etiology of CRC, autophagy is an important transformational switch that occurs when a cell shifts from normal to malignant. In recent years, multiple hypotheses have been considered regarding the autophagy mechanisms that are involved in cancer. The currently accepted hypothesis is that autophagy has dual and contradictory roles in carcinogenesis, but the precise mechanisms leading to autophagy in cancer are not yet fully defined and seem to be context dependent. Autophagy is a surveillance mechanism used by normal cells that protects them from the transformation to malignancy by removing damaged organelles and aggregated proteins and by reducing reactive oxygen species, mitochondrial abnormalities and DNA damage. However, autophagy also supports tumor formation by promoting access to nutrients that are critical to the metabolism and growth of tumor cells and by inhibiting cellular death and increasing drug resistance. Autophagy studies in CRC have focused on several molecules, mainly microtubule-associated protein 1 light chain 3, beclin 1, and autophagy related 5, with conflicting results. Beneficial effects were observed for some agents that modulate autophagy in CRC either alone or, more often, in combination with other agents. More extensive studies are needed in the future to clarify the roles of autophagy-related genes and modulators in colorectal carcinogenesis, and to develop potential beneficial agents for the prognosis and treatment of CRC.     

Role of Autophagy as a Survival Mechanism for Hypoxic Cells in Tumors

Enhanced autophagy has been observed in hypoxic regions of solid tumors. Here we address the hypothesis that autophagy is required for survival of hypoxic cells. We evaluated sensitivity to hypoxia of three human tumor cell lines (MCF7, PC3, and LNCaP) and their autophagy-deficient variants with shRNA knockdown of the genes ATG7 and BECLIN1. Hypoxia-induced cell death was more rapid for autophagy-deficient cells and was increased in the presence of the proton pump inhibitor pantoprazole that inhibits autophagy. Autophagy-deficient cells had a lower rate of oxygen consumption than wild-type cells. In xenografts derived from the three cell lines, autophagy (as determined by increased LC3 and reduced p62/SQSTM1) colocalized with hypoxic regions (identified by EF5). Xenografts derived from autophagy-deficient cells grew more slowly than wild-type tumors. Both LC3 expression and hypoxia were decreased in xenografts generated from single-knockdown cells and absent in double-knockdown tumors. Our results are consistent with the hypothesis that autophagy facilitates the survival of hypoxic cells, although reduced oxygen consumption of autophagy-deficient cells may contribute to lack of hypoxia in tumors derived from them. Because hypoxia is associated with resistance to anticancer therapy, inhibition of autophagy has potential to enhance the effectiveness of cancer treatment.