A critical role for autophagy in pancreatic cancer

Autophagy is a regulated catabolic process that leads to the lysosomal degradation of damaged proteins, organelles and other macromolecules, with subsequent recycling of bioenergetic intermediates. The role of autophagy in cancer is undoubtedly complex and likely dependent on tumor type and on the cellular and developmental context. While it has been well demonstrated that autophagy may function as a tumor suppressor, there is mounting evidence that autophagy may have pro-tumorigenic roles, e.g., promoting therapeutic resistance as well as survival under stresses such as hypoxia and nutrient deprivation. These two, seemingly disparate functions can be reconciled by a possible temporal role of autophagy during tumor development, initially suppressing tumor initiation yet supporting tumor growth at later stages.     

Why sick cells produce tumors: the protective role of autophagy

Cells exploit autophagy for survival to metabolic stress in vitro as well as in tumors where it localizes to regions of metabolic stress suggesting its role as a survival pathway. Consistent with this survival function, deficiency in autophagy impairs cell survival, but also promotes tumor growth, creating a paradox that the loss of a survival pathway leads to tumorigenesis. There is evidence that autophagy is a homeostatic process functioning to limit the accumulation of poly-ubiquitinated proteins and mutant protein aggregates associated with neuronal degeneration. Interestingly, we found that deficiency in autophagy caused by monoallelic loss of beclin1 or deletion of atg5 leads to accelerated DNA damage and chromosomal instability demonstrating a mutator phenotype. These cells also exhibit enhanced chromosomal gains or losses suggesting that autophagy functions as a tumor suppressor by limiting chromosomal instability. Thus the impairment of survival to metabolic stress due to deficiency in autophagy may be compensated by an enhanced mutation rate thereby promoting tumorigenesis. The protective role of autophagy may be exploited in developing novel autophagy modulators as rational chemotherapeutic as well as chemopreventive agents.     

Interplay between apoptosis and autophagy,a challenging puzzle: New perspectives on antitumor chemotherapies

Autophagy is a mechanism of protection against various forms of human diseases, such as cancer, in which autophagy seems to have an extremely complex role. In cancer, there is evidence that autophagy may be oncogenic in some contexts, whereas in others it clearly contributes to tumor suppression. In addition, studies have demonstrated the existence of a complex relationship between autophagy and cell death, determining whether a cell will live or die in response to anticancer therapies. Nevertheless, we still need to complete the autophagy–apoptosis puzzle in the tumor context to better address appropriate chemotherapy protocols with autophagy modulators. Generally, tumor cell resistance to anticancer induced-apoptosis can be overcome by autophagy inhibition. However, when an extensive autophagic stimulus is activated, autophagic cell death is observed. In this review, we discuss some details of autophagy and its relationship with tumor progression or suppression, as well as role of autophagy–apoptosis in cancer treatments.     

Why Sick Cells Produce Tumors: The Protective Role of Autophagy

Cells exploit autophagy for survival to metabolic stress in vitro as well as in tumors where it localizes to regions of metabolic stress suggesting its role as a survival pathway. Consistent with this survival function, deficiency in autophagy impairs cell survival, but also promotes tumor growth, creating a paradox that the loss of a survival pathway leads to tumorigenesis. There is evidence that autophagy is a homeostatic process functioning to limit the accumulation of poly-ubiquitinated proteins and mutant protein aggregates associated with neuronal degeneration. Interestingly, we found that deficiency in autophagy caused by monoallelic loss of beclin1 or deletion of atg5 leads to accelerated DNA damage and chromosomal instability demonstrating a mutator phenotype. These cells also exhibit enhanced chromosomal gains or losses suggesting that autophagy functions as a tumor suppressor by limiting chromosomal instability. Thus the impairment of survival to metabolic stress due to deficiency in autophagy may be compensated by an enhanced mutation rate thereby promoting tumorigenesis. The protective role of autophagy may be exploited in developing novel autophagy modulators as rational chemotherapeutic as well as chemopreventive agents.

Addendum to:

Autophagy Supresses Tumor Progression by Limiting Chromosomal Instability

R. Mathew, S. Kongara, B. Beaudoin, C.M. Karp, K. Bray, K. Degenhardt, G. Chen, S. Jin and E. White

Genes Dev 2007; 21:1367-81     

Mechanisms and context underlying the role of autophagy in cancer metastasis

Macroautophagy/autophagy is a fundamental cellular degradation mechanism that maintains cell homeostasis, regulates cell signaling, and promotes cell survival. Its role in promoting tumor cell survival in stress conditions is well characterized, and makes autophagy an attractive target for cancer therapy. Emerging research indicates that autophagy also influences cancer metastasis, which is the primary cause of cancer-associated mortality. However, data demonstrate that the regulatory role of autophagy in metastasis is multifaceted, and includes both metastasis-suppressing and -promoting functions. The metastasis-suppressing functions of autophagy, in particular, have important implications for autophagy-based treatments, as inhibition of autophagy may increase the risk of metastasis. In this review, we discuss the mechanisms and context underlying the role of autophagy in metastasis, which include autophagy-mediated regulation of focal adhesion dynamics, integrin signaling and trafficking, Rho GTPase-mediated cytoskeleton remodeling, anoikis resistance, extracellular matrix remodeling, epithelial-to-mesenchymal transition signaling, and tumor-stromal cell interactions. Through this, we aim to clarify the context-dependent nature of autophagy-mediated metastasis and provide direction for further research investigating the role of autophagy in cancer metastasis.     

Ubiquitin networks in cancer

Conjugation of ubiquitin to cellular proteins has emerged as a post-translational modification, which affects major cellular processes, including cell cycle, proliferation and apoptosis. The ubiquitin-mediated signaling is frequently altered in cancer cells, with several tumor suppressors and oncogenes representing enzymes of the ubiquitin conjugation and deconjugation pathways. Recently, ubiquitination has been involved into selective degradation of both proteins and mitochondria by autophagy. Studying this novel role of ubiquitin can shed light on autophagy as a tumor suppressor mechanism as well as provide insights into the role of autophagy in survival of tumor cells, thus aiding the design of better cancer therapies.     

Autophagy,senescence and tumor dormancy in cancer therapy

The relationships between autophagy and apoptosis have been examined quite extensively and have often been shown to be reciprocally regulated responses to stresses such as exposure of the tumor cells to chemotherapeutic drugs and radiation. However, there is now evidence that autophagy may also play a role in tumor dormancy. Given that tumor dormancy and disease recurrence are poorly understood phenomenon which are nevertheless critical elements of patient morbidity and mortality, this commentary develops the postulate that autophagy and senescence may be related responses that influence the capacity of the tumor cell to maintain a prolonged state of growth arrest that can be succeeded by tumor regrowth and disease recurrence.     

Inhibition of autophagy impairs tumor cell invasion in an organotypic model

Autophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. It contributes to energy and organelle homeostasis and the preservation of proteome and genome integrity. Although a role in cancer is unquestionable, there are conflicting reports that autophagy can be both oncogenic and tumor suppressive, perhaps indicating that autophagy has different roles at different stages of tumor development. In this report, we address the role of autophagy in a critical stage of cancer progression—tumor cell invasion. Using a glioma cell line containing an inducible shRNA that targets the essential autophagy gene Atg12, we show that autophagy inhibition does not affect cell viability, proliferation or migration but significantly reduces cellular invasion in a 3D organotypic model. These data indicate that autophagy may play a critical role in the benign to malignant transition that is also central to the initiation of metastasis.     

Inhibition of autophagy impairs tumor cell invasion in an organotypic model

Autophagy is a membrane-trafficking process that delivers cytoplasmic constituents to lysosomes for degradation. It contributes to energy and organelle homeostasis and the preservation of proteome and genome integrity. Although a role in cancer is unquestionable, there are conflicting reports that autophagy can be both oncogenic and tumor suppressive, perhaps indicating that autophagy has different roles at different stages of tumor development. In this report, we address the role of autophagy in a critical stage of cancer progression—tumor cell invasion. Using a glioma cell line containing an inducible shRNA that targets the essential autophagy gene Atg12, we show that autophagy inhibition does not affect cell viability, proliferation or migration but significantly reduces cellular invasion in a 3D organotypic model. These data indicate that autophagy may play a critical role in the benign to malignant transition that is also central to the initiation of metastasis.     

p53, Autophagy and Tumor Suppression

Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy.     

p53, Autophagy and tumor suppression

Autophagy was recently established as a novel tumor suppression mechanism, which stimulated a wave of investigations that were aimed at understanding exactly how autophagy prevents tumorigenesis, as well as to determine to what extent autophagy is implicated in human cancers. Autophagy might exert its tumor suppression function at the subcellular level by removing defective cytoplasmic components, such as damaged mitochondria. In addition, it might function at the cellular level by helping in the orderly removal of damaged cells. Previous studies indicated that autophagy is compromised in human breast, ovarian and prostate cancers. Recent research revealed that autophagy is activated by p53, a critical tumor suppressor that is involved in most, if not all, tumorigenesis. This study places autophagy in a broader context of human cancers. Future work elucidating the role of autophagy in the p53 circuit and p53 function might provide more insight into tumorigenesis and targeted cancer chemotherapy.     

Paradoxical role of autophagy in the dysplastic and tumor-forming stages of hepatocarcinoma development in rats

Many reports have shown that autophagy has a role as both a promoter and inhibitor in tumor development. However, the mechanism of this paradox is unknown. Tumor development is a multistep process. Therefore, we investigated whether the role of autophagy in hepatocarcinoma formation depended on the stage of tumor development. Based on our results, autophagy inhibition by chloroquine had a tumor-promotive effect in the rat model with N-diethylnitrosamine-induced hepatocarcinogenesis in its dysplastic stage (Ds) and a tumor-suppressive effect in its tumor-forming stage (Ts). In the Ds, autophagy inhibition enhanced cell proliferation, DNA damage and inflammatory cytokines expression in liver. These changes were dependent on the upregulation of reactive oxygen species (ROS) that was resulted from autophagy inhibition, and ultimately accelerated the process of hepatocarcinogenesis. However, in the Ts, autophagy inhibition restrained tumor formation by decreasing tumor cell survival and proliferation. In this stage, autophagy inhibition led to excessive ROS accumulation in the tumor, which promoted cell apoptosis, and prominently suppressed tumor cell metabolism. Taken together, our data suggested that autophagy suppressed hepatocarcinogenesis in the Ds by protecting normal cell stability and promoted hepatocarcinogenesis in the Ts by supporting tumor cells growth. Autophagy always had a role as a protector throughout the process of hepatocarcinoma development.     

Autophagy-mediated regulation of macrophages and its applications for cancer

Autophagy is a highly conserved homeostatic pathway that plays an important role in tumor development and progression by acting on cancer cells in a cell-autonomous mechanism. However, the solid tumor is not an island, but rather an ensemble performance that includes nonmalignant stromal cells, such as macrophages. A growing body of evidence indicates that autophagy is a key component of the innate immune response. In this review, we discuss the role of autophagy in the control of macrophage production at different stages (including hematopoietic stem cell maintenance, monocyte/macrophage migration, and monocyte differentiation into macrophages) and polarization and discuss how modulating autophagy in tumor-associated macrophages (TAMs) may represent a promising strategy for limiting cancer growth and progression.     

Tumor suppression by autophagy through the management of metabolic stress

Autophagy plays a critical protective role maintaining energy homeostasis and protein and organelle quality control. These functions are particularly important in times of metabolic stress and in cells with high energy demand such as cancer cells. In emerging cancer cells, autophagy defect may cause failure of energy homeostasis and protein and organelle quality control, leading to the accumulation of cellular damage in metabolic stress. Some manifestations of this damage, such as activation of the DNA damage response and generation of genome instability may promote tumor initiation and drive cell-autonomous tumor progression. In addition, in solid tumors, autophagy localizes to regions that are metabolically stressed. Defects in autophagy impair the survival of tumor cells in these areas, which is associated with increased cell death and inflammation. The cytokine response from inflammation may promote tumor growth and accelerate cell non-autonomous tumor progression. The overreaching theme is that autophagy protects cells from damage accumulation under conditions of metabolic stress allowing efficient tolerance and recovery from stress, and that this is a critical and novel tumor suppression mechanism. The challenge now is to define the precise aspects of autophagy, including energy homeostasis and protein and organelle turnover, that are required for the proper management of metabolic stress that suppress tumorigenesis. Furthermore, we need to be able to identify human tumors with deficient autophagy, and to develop rational cancer therapies that take advantage of the altered metabolic state and stress responses inherent to this autophagy defect.     

The role of autophagy in the metabolism and differentiation of stem cells

Autophagy is a very well-coordinated intracellular process that maintains cellular homeostasis under basal conditions by removing unnecessary or dysfunctional components through orderly degradation and recycling. Under pathological conditions, defects in autophagy have been linked to various human disorders, including neurodegenerative disorders and cancer. The role of autophagy in stem cell proliferation, differentiation, self-renewal, and senescence is well documented. Additionally, cancer stem cells (CSCs) play an important role in tumorigenesis, metastasis and tumor relapse and several studies have suggested the involvement of autophagy in the maintenance and invasiveness of CSCs. Hence, considering the modulation of autophagy in normal and cancer stems cells as a therapeutic approach can lead to the development or improvement of regenerative and anti-cancer therapies. Accordingly, modulation of autophagy can be regarded as a target for stem cell-based therapy of diseases with abnormal levels of autophagy.This article is focused on understanding the role of autophagy in stem cell homeostasis with an emphasis on the therapeutic potential of targeting autophagy for future therapies.     

Regulation of mitochondrial integrity, autophagy and cell survival by BNIP3

Understanding the role of BNIP3 in the systemic response to hypoxia has been complicated by conflicting results that indicate on the one hand that BNIP3 promotes cell death, and other data, including our own that BNIP3 is not sufficient for cell death, but rather plays a critical role in hypoxia-induced autophagy. This work suggests that rather than promoting death, BNIP3 may actually allow survival either by preventing ATP depletion or by eliminating damaged mitochondria. However, the function of BNIP3 may be subverted under unusual conditions associated with acidosis that arise following extended periods of hypoxia and anaerobic glycolysis. Despite this novel insight into BNIP3 function, much remains to be done in terms of pinning down a molecular activity for BNIP3 that explains both its role in autophagy and how this may be subverted to induce cell death. As a target of the RB tumor suppressor, our work also places BNIP3 at the center of efforts to exploit autophagy to better treat human cancers in which tumor hypoxia is implicated as a progression factor.     

自噬与肿瘤关系的研究与进展

自噬是一个高度发达而且十分保守的生物学分解代谢过程。自噬与肿瘤的关系十分密切,在肿瘤发生发展的过程中,自噬活性的改变却是一把双刃剑。自噬,它既能够使肿瘤细胞耐受不同的应激条件而使其获得更好的生存,也可以通过各种信号途径减轻许多不良应激条件下的细胞损伤,如慢性炎症、慢性细胞死亡及基因组损伤等,从而而减少肿瘤的发生。再者,一方面,某些肿瘤的发生和发展过程中也同样依赖于自噬,并且肿瘤细胞可以利用自噬来对抗抗癌药物的一定的细胞毒性。而另一方面,有些癌症却需要利用自噬的作用来杀死肿瘤细胞。虽然自噬与肿瘤的关系是十分复杂的,也存在不少的分歧,但总的来说自噬在癌症中的作用是至关重要的。结合近年来国内外研究的发展,我们这篇综述重点讨论的是自噬在癌症中的作用,并且探讨其潜在的作用机制,以及目前自噬在癌症治疗中的应用。     

The autophagic tumor stroma model of cancer or “battery-operated tumor growth”

The role of autophagy in tumorigenesis is controversial. Both autophagy inhibitors (chloroquine) and autophagy promoters (rapamycin) block tumorigenesis by unknown mechanism(s). This is called the “Autophagy Paradox”. We have recently reported a simple solution to this paradox. We demonstrated that epithelial cancer cells use oxidative stress to induce autophagy in the tumor microenvironment. As a consequence, the autophagic tumor stroma generates recycled nutrients that can then be used as chemical building blocks by anabolic epithelial cancer cells. This model results in a net energy transfer from the tumor stroma to epithelial cancer cells (an energy imbalance), thereby promoting tumor growth. This net energy transfer is both unilateral and vectorial, from the tumor stroma to the epithelial cancer cells, representing a true host-parasite relationship. We have termed this new paradigm “The Autophagic Tumor Stroma Model of Cancer Cell Metabolism” or “Battery-Operated Tumor Growth”. In this sense, autophagy in the tumor stroma serves as a “battery” to fuel tumor growth, progression, and metastasis, independently of angiogenesis. Using this model, the systemic induction of autophagy will prevent epithelial cancer cells from using recycled nutrients, while the systemic inhibiton of autophagy will prevent stromal cells from producing recycled nutrients—both effectively “starving” cancer cells. We discuss the idea that tumor cells could become resistant to the systemic induction of autophagy, by the up-regulation of natural endogenous autophagy inhibitors in cancer cells. Alternatively, tumor cells could also become resistant to the systemic induction of autophagy, by the genetic silencing/deletion of pro-autophagic molecules, such as Beclin1. If autophagy resistance develops in cancer cells, then the systemic inhibition of autophagy would provide a therapeutic solution to this type of drug resistance, as it would still target autophagy in the tumor stroma. As such, an anti-cancer therapy that combines the alternating use of both autophagy promoters and autophagy inhibitors would be expected to prevent the onset of drug resistance. We also discuss why anti-angiogenic therapy has been found to promote tumor recurrence, progression, and metastasis. More specifically, anti-angiogenic therapy would induce autophagy in the tumor stroma via the induction of stromal hypoxia, thereby converting a non-aggressive tumor type to a “lethal” aggressive tumor phenotype. Thus, uncoupling the metabolic parasitic relationship between cancer cells and an autophagic tumor stroma may hold great promise for anti-cancer therapy. Finally, we believe that autophagy in the tumor stroma is the local microscopic counterpart of systemic wasting (cancer-associated cachexia), which is associated with advanced and metastatic cancers. Cachexia in cancer patients is not due to decreased energy intake, but instead involves an increased basal metabolic rate and increased energy expenditures, resulting in a negative energy balance. Importantly, when tumors were surgically excised, this increased metabolic rate returned to normal levels. This view of cachexia, resulting in energy transfer to the tumor, is consistent with our hypothesis. So, cancer-associated cachexia may start locally as stromal autophagy, and then spread systemically. As such, stromal autophagy may be the requisite precursor of systemic cancer-associated cachexia.