A critical role for autophagy in pancreatic cancer

Division of Genomic Stability and DNA Repair, Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Autophagy (Impact Factor: 11.75). 08/2011; 7(8):912-3. DOI: 10.4161/auto.7.8.15762
Source: PubMed


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.

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    • "Under these conditions, autophagy could be activated by tumor cells to degrade cellular contents and provide substrate for energy production. There is considerable evidence that abnormal autophagy promotes the progression of many solid tumors and is negatively correlated with the prognosis (Yang et al., 2011; Liu and Ryan, 2012). Abnormal autophagy may also make a contribution to the acquisition of drug resistance (Chen and Karantza, 2011; Ding et al., 2011). "
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    ABSTRACT: Microtubule-associated protein light chain 3 (LC3A) is a reliable marker of autophagy that displays three distinct patterns of immunohistochemical staining in solid tumors: diffuse cytoplasmic staining, juxtanuclear staining, and staining of "stone-like" structures. These three patterns have a different prognostic significance in many solid tumors, but little is known about their influence in gastric cancer (GC). This study was a retrospective analysis of 188 GC patients from stages I to IV. The pattern of LC3A expression was examined in tumor and nontumor tissues by immunohistochemistry. Then, the association between the pattern of LC3A expression in GC and the prognosis was investigated by Kaplan-Meier analysis and the Cox proportional hazards model. Two distinct patterns of LC3A immunostaining (diffuse cytoplasmic expression and "stone-like" structures) were observed in GC tissues. LC3A-positive "stone-like" structures were found only in the tumors, and the number of such structures was correlated with both the tumor type and tumor stage. In addition, a high number of LC3A-positive "stone-like" structures was closely associated with an increased risk of recurrence after radical resection of stages I-III cancer (P < 0.001; HR = 0.205) and was associated with a lower overall survival rate for stage IV cancer (P < 0.001; HR = 0.364). Taken together, our data demonstrate that LC3A-positive "stone-like" structures can be used as an independent biomarker for an adverse prognosis of GC, suggesting that "stone-like" structures are correlated with the malignancy of this disease. Anat Rec, 00:000-000, 2014. © 2014 The Authors The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology Published by Wiley Periodicals, Inc.
    Full-text · Article · Apr 2014 · The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology
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    • "Badania in vivo i in vitro wykazały, że próby jej zahamowania spowodowały statystycznie wzrost przeżycia. Wyniki badań pokazują ponadto, że autofagia może ochronić komórki rakowe przed promieniowaniem jonizacyjnym , między innymi poprzez usunięcie uszkodzonych organelli, takich jak mitochondria, które biorą udział w procesie apoptozy i nie pozwalają przez to na przetrwanie stransformowanych pod wpływem tego promieniowania komórek [80] [81]. Stwierdzono także, że autofagia może ułatwiać przeżycie komórek nowotworowych po ich oderwaniu od podłoża. "
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    ABSTRACT: Autophagy is a process that is involved in the pathogenesis of cancer but also in the development of resistance or sensitivity to cytostatic treatment applied. Until now, the issue is still unresolved if we should stimulate or inhibit the process of autophagy in cancer treatment through the use of appropriate anticancer therapy so that it is beneficial for the patient and induce remission of the disease. On the one hand autophagy as a mechanism of programmed cell death may also cause the death of tumor cells. On the other hand, as a defense mechanism is the process of cell survival strategy in stress situations such as hypoxia in the peripheral parts of the tumor or using cytostatic drugs. It would be good to find an answer if the autophagy is the process increasing the effectiveness of therapy or increasing resistance to treatment in a case of specific tumor.
    Preview · Article · Oct 2013 · Acta haematologica Polonica
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    • "As the tumor environment is hypoxic, autophagy is often induced by hypoxia-inducible factor-α signaling, or adenosine monophosphate activated protein kinase (AMPK), the latter also being associated with pancreatitis (Shugrue et al., 2012). Elevated levels of autophagy in PDAC cells are critical in removal of ROS, preventing DNA damage and maintaining energy homeostasis, thus optimizing PDAC cell survival and proliferation (Yang and Kimmelman, 2011). "
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    ABSTRACT: Purpose of the review: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer. Recent findings: Intracellular activation of both pancreatic enzymes and the transcription factor NF-κB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer. Summary: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.
    Full-text · Article · Jan 2013 · Frontiers in Physiology
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