[PDF] Self Eating On Demand Autophagy In Cancer And Cancer Therapy eBook
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Macroautophagy, the major lysosomal pathway for recycling intracellular components including whole organelles, has emerged as a key process modulating tumorigenesis, tumor–stroma interactions, and cancer therapy. An impressive number of studies over the past decade have unraveled the plastic role of autophagy during tumor development and dissemination. The discoveries that autophagy may either support or repress neoplastic growth and contextually favor or weaken resistance and impact antitumor immunity have spurred efforts from many laboratories trying to conceptualize the complex role of autophagy in cancer using cellular and preclinical models. This complexity is further accentuated by recent findings highlighting that various autophagy-related genes have roles beyond this catabolic mechanism and interface with oncogenic pathways, other trafficking and degradation mechanisms and the cell death machinery. From a therapeutic perspective, knowledge of how autophagy modulates the tumor microenvironment is crucial to devise autophagy-targeting strategies using smart combination of drugs or anticancer modalities. This eBook contains a collection of reviews by autophagy researchers and provides a background to the state-of-the-art in the field of autophagy in cancer, focusing on various aspects of autophagy regulation ranging from its molecular components to its cell autonomous role, e.g. in cell division and oncogenesis, miRNAs regulation, cross-talk with cell death pathways as well as cell non-autonomous role, e.g. in secretion, interface with tumor stroma and clinical prospects of autophagy-based biomarkers and autophagy modulators in anticancer therapy. This eBook is part of the TransAutophagy initiative to better understand the clinical implications of autophagy in cancer.
Macroautophagy, the major lysosomal pathway for recycling intracellular components including whole organelles, has emerged as a key process modulating tumorigenesis, tumor-stroma interactions, and cancer therapy. An impressive number of studies over the past decade have unraveled the plastic role of autophagy during tumor development and dissemination. The discoveries that autophagy may either support or repress neoplastic growth and contextually favor or weaken resistance and impact antitumor immunity have spurred efforts from many laboratories trying to conceptualize the complex role of autophagy in cancer using cellular and preclinical models. This complexity is further accentuated by recent findings highlighting that various autophagy-related genes have roles beyond this catabolic mechanism and interface with oncogenic pathways, other trafficking and degradation mechanisms and the cell death machinery. From a therapeutic perspective, knowledge of how autophagy modulates the tumor microenvironment is crucial to devise autophagy-targeting strategies using smart combination of drugs or anticancer modalities. This eBook contains a collection of reviews by autophagy researchers and provides a background to the state-of-the-art in the field of autophagy in cancer, focusing on various aspects of autophagy regulation ranging from its molecular components to its cell autonomous role, e.g. in cell division and oncogenesis, miRNAs regulation, cross-talk with cell death pathways as well as cell non-autonomous role, e.g. in secretion, interface with tumor stroma and clinical prospects of autophagy-based biomarkers and autophagy modulators in anticancer therapy. This eBook is part of the TransAutophagy initiative to better understand the clinical implications of autophagy in cancer.
A solid cancerous tumor is a complex mixture of many different cell types, varying compositions of extracellular matrix, and fluctuating degrees of oxygen and nutrient availability. This heterogeneity generates distinct stress-inducing tumor microenvironments (TME) that add selective pressure on cancer cells, selecting aggressive cancer cells that have an advantage of survival or metastatic potential. To survive stressful TMEs, cancer cells utilize an evolutionary conserved intracellular degradation and recycling mechanism, called autophagy (from the Greek for self-eating). Autophagy uses double membraned vesicles, called autophagosomes, to engulf cytoplasmic cargo for delivery to the lysosome for degradation. In general, autophagy is thought to promote cancer cell survival by facilitating the degradation of various cytoplasmic components and recycling of essential nutrients in starvation conditions, making it an attractive therapeutic strategy for treating cancers. However, the precise role of autophagy within the TME is controversial, as it exhibits both tumor-promoting and tumor-suppressing phenotypes, making it difficult to conclude whether autophagy is a viable target for cancer therapy. In particular, this paradox is most evident in regards to the role of autophagy in regulating cancer metastasis, as reports conflict as to whether autophagy is truly a metastasis-suppressing or -promoting pathway. Emerging research indicates that the influence of autophagy on cancer progression is dependent on several factors, including cancer cell type and the TME. Thus, more physiologically relevant assessments which incorporate TME-associated stress and cell-to-cell interactions are needed to better understand the role of autophagy in tumor progression. Accordingly, the primary focus of this doctoral dissertation involves elucidating the role of autophagy in tumor progression in the context of hypoxia (i.e. low oxygen conditions), a hallmark of the TME. In chapter 2, we explored the impact of autophagy on the pathophysiology of breast cancer cells, using a novel hypoxia-dependent, reversible dominant negative strategy to regulate autophagy at the cellular level within the TME. Suppression of autophagy via hypoxia-induced expression of the kinase-dead dominant-negative mutant of ULK1 (dnULK1K49R) increased lung metastases in MDA-MB-231 xenograft mouse models. Consistent with this effect, expressing a dominant-negative mutant of ULK1 or ATG4b or a ULK1-targeting shRNA facilitated cell migration in vitro. Functional proteomic and transcriptome analysis revealed that loss of hypoxia-regulated autophagy promotes metastasis via induction of the fibronectin integrin signaling axis. In agreement, loss of ULK1 function increased fibronectin deposition in the hypoxic TME. Additionally, we report that low expression of autophagy genes predicts a worse prognosis in human breast cancer. Together, our results indicated that hypoxia-regulated autophagy suppresses metastasis in breast cancer by preventing tumor fibrosis. These results also suggest caution in the development of autophagy-based strategies for cancer treatment. In addition to this, a secondary focus of this dissertation involved examining the translational implications of targeting autophagy for therapeutic benefit in neuroblastoma, a cancer of immature nerve cells that predominantly effects children under five years old. In chapter 3, we demonstrate that targeted inhibition of an essential autophagy kinase, ULK1, with a recently developed small molecular inhibitor of ULK1, SBI-0206965, significantly reduces cell growth and promotes apoptosis in SK-N-AS, SH-SY5Y, and SK-N-DZ neuroblastoma cell lines. Furthermore, inhibition of ULK1 by a dominant-negative mutant of ULK1 (dnULK1K49R) significantly reduced growth and metastatic disease and prolonged survival of mice bearing SK-N-AS xenograft tumors. We also show that SBI-0206965 sensitized SK-N-AS cells to TRAIL treatment, but not mTOR inhibitors (INK128, Torin1) or topoisomerase inhibitors (doxorubicin, topotecan). Collectively, these findings demonstrate that ULK1 is a viable drug target and inhibitors of ULK1 may provide a novel therapeutic option for the treatment of neuroblastoma. Furthermore, this work demonstrates the antitumor effects of targeting an essential autophagy gene in neuroblastoma mouse models.In summation, this dissertation has elucidated that hypoxia-regulated autophagy acts to suppress metastasis in breast cancer, and demonstrated that ULK1 kinase is a viable drug target for the treatment of neuroblastoma. Collectively, this work has further defined the complex role of autophagy in tumor biology, as well as provided pre-clinical data that may aid in the development of novel treatment options for cancer patients.
(Macro)autophagy is a catabolic process whereby intracellular components are enclosed into autophagosomes and delivered to lysosomes for degradation. Constitutive activity of autophagy contributes to turnover of proteins and organelles, ensuring the quality control of cellular components. Autophagy also can be induced by starvation or other stresses. This activity serves to provide internal resources to sustain metabolism and to prevent accumulation of detrimental substances. Therefore, autophagy is critical for cells to maintain homeostasis and to survive stress. Tumors are often subjected to metabolic stress due to insufficient vascularization. Autophagy is induced and localizes to these hypoxic regions where it supports survival. In aggressive tumors, the increased metabolic demand of rapid proliferation and growth may augment the dependency of cells on autophagy. In addition, autophagy that is induced by cancer therapy may be utilized by tumor cells for survival and be counterproductive to therapeutic efficacy. In this work, we tested the hypothesis that autophagy enables tumor cell survival and tumorigenesis in two different settings and addressed the underlying mechanism by which this occurs. First, we demonstrated that autophagy is required for viability in starvation and tumorigenicity of cells with oncogenic Ras activation. In these cells, defective autophagy caused abnormal mitochondria accumulation and reduced mitochondrial functionality in starvation associated with reduced energy charge. Since mitochondrial function is required for survival during starvation, we reasoned that autophagy supports survival and tumorigenicity of Ras-expressing cells by maintaining mitochondrial functionality. We also demonstrated that autophagy maintained mitochondrial function by preserving functional mitochondrial pools through mitophagy as well as by providing substrates for mitochondrial bioenergetic production under stress, thereby identifying autophagy and mitophagy as potential targets for treatment of cancers with oncogenic Ras activation. Second, we examined the significance of the mTOR inhibition-induced autophagy in counteracting the efficacy of the mTOR inhibitor CCI-779, which has shown temporary effectiveness in clinical treatment of human renal cell carcinoma. We demonstrated that mTOR inhibition promoted autophagy-mediated stress tolerance. Inhibition of autophagy with chloroquine enhanced the cytotoxicity of CCI-779 in vitro and in allograft tumors in mice. We further demonstrated that autophagy promoted cell survival in CCI-779-treated cells by providing alternative substrates for mitochondrial metabolism and suppressing reactive oxygen species production. This result justified a combination of autophagy inhibition with mTOR inhibitors in cancer therapy.
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. Presents the most advanced information regarding the role of the autophagic system in life and death Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available
This book deals with the paradoxical role of autophagy in tumor suppression and tumor promotion in cancer cells. Autophagy plays opposing, context-dependent roles in tumors; accordingly, strategies based on inhibiting or stimulating autophagy could offer as potential cancer therapies. The book elucidates the physiological role of autophagy in modulating cancer metastasis, which is the primary cause of cancer-associated mortality. Further, it reviews its role in the differentiation, development, and activation of multiple immune cells, and its potential applications in tumor immunotherapy. In addition, it examines the effect of epigenetic modifications of autophagy-associated genes in regulating tumor growth and therapeutic response and summarizes autophagy’s role in the development of resistance to a variety of anti-cancer drugs in cancer cells. In closing, it assesses autophagy as a potential therapeutic target for cancer treatment. Given its scope, the book offers a valuable asset for all oncologists and researchers who wish to understand the potential role of autophagy in tumor biology.
This book explores potential cellular drug targets for cancer therapy. The first couple of chapters describe conventional treatment (radiotherapy, chemotherapy, and immunotherapy) & detection (biosensors) strategies for cancer. In contrast, the subsequent chapters address the role of cyclin-dependent kinases and cell cycle regulatory proteins in the growth of cancer cells and their potential as target for cancer treatment. The book then discusses the regulation of various pro-apoptotic and anti-apoptotic proteins via chemotherapeutic drugs. In addition, it examines the molecular mechanisms that are critical for mediating autophagic cell death in cancer cells. It subsequently reviews the role of reactive oxygen (ROS) species during carcinogenesis and during chemotherapy, and the potential of anti-inflammatory routes for the development of new therapeutic modulators. Lastly, it describes therapeutic strategies that target the tumor microenvironment and various angiogenic pathways for the treatment of cancer and to develop personalized medicine. Given its scope, the book is valuable resource for oncologists, cancer researchers, clinicians, and pharmaceutical industry personnel.
Advances in Cancer Research, Volume 150, the latest release in this ongoing series, covers the relationship(s) between autophagy and senescence, how they are defined, and the influence of these cellular responses on tumor dormancy and disease recurrence. Specific sections in this new release include Autophagy and senescence, converging roles in pathophysiology, Cellular senescence and tumor promotion: role of the unfolded protein response, autophagy and senescence in cancer stem cells, Targeting the stress support network regulated by autophagy and senescence for cancer treatment, Autophagy and PTEN in DNA damage-induced senescence, mTOR as a senescence manipulation target: A forked road, and more. Addresses the relationship between autophagy and senescence in cancer therapy Covers autophagy and senescence in tumor dormancy Explores autophagy and senescence in disease recurrence
With the explosion of information on autophagy in cancer, this is an opportune time to speed the efforts to translate our current knowledge about autophagy regulation into better understanding of its role in cancer. This book will cover the latest advances in this area from the basics, such as the molecular machinery for autophagy induction and regulation, up to the current areas of interest such as modulation of autophagy and drug discovery for cancer prevention and treatment. The text will include an explanation on how autophagy can function in both oncogenesis and tumor suppression and a description of its function in tumor development and tumor suppression through its roles in cell survival, cell death, cell growth as well as its influences on inflammation, immunity, DNA damage, oxidative stress, tumor microenvironment, etc. The remaining chapters will cover topics on autophagy and cancer therapy. These pages will serve as a description on how the pro-survival function of autophagy may help cancer cells resist chemotherapy and radiation treatment as well as how the pro-death functions of autophagy may enhance cell death in response to cancer therapy, and how to target autophagy for cancer prevention and therapy − what to target and how to target it.