[PDF] Modulation Of Autophagy And Senescence To Enhance The Response To Therapy In Triple Negative Breast Cancer eBook

Author : Liliya Tyutyunyk-Massey
Publisher :
Page : pages
File Size : 38,69 MB
Release : 2019
Category :
ISBN :

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Abstract Although great strides have been made over the decades in development and optimization of anti-cancer therapies, even highly effective drugs often fail to completely eliminate tumors. Residual tumor cells can enter into a state of dormancy for prolonged periods of time but eventually are able to regain proliferative capacity and reemerge as chemotherapy-resistant disease. Because recurrent disease is a leading contributor to patient's mortality, it is paramount to identify strategies for effectively destroying residual tumor cells. Cytotoxic drugs and ionizing radiation are used as standard therapies in a variety of cancers. These modalities induce apoptosis, autophagy and senescence. Senescence is a state of prolonged growth arrest, which cells are able to eventually escape regaining proliferative capacity. Autophagy is generally considered to be a protective mechanism; however, it can take non-protective or even cytotoxic form in response to anti-cancer treatments. Furthermore, chemotherapy or radiation induced autophagy was shown to be a contributor to the immune response against tumor cells. Using a model of Triple Negative Breast Cancer, we were able to show increased immunosurveillance of tumor cells after enhanced autophagy was achieved by combining epigenetic remodeling with chemotherapy. Alternatively, we were able to achieved effective clearance of tumor cells induced into senescence by chemotherapy or radiation by the senolytic drug ABT-263 (Navitoclax). In summary, autophagy and senescence alone or in concert, can be induced by conventional anti-tumor modalities. Those processes can be modulated independently to achieve clearance of residual tumor cells following anti-cancer therapies.

Author :
Publisher : Academic Press
Page : 384 pages
File Size : 31,2 MB
Release : 2021-04-13
Category : Medical
ISBN : 0128241594

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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

Author : Patrizia Agostinis
Publisher : Frontiers Media SA
Page : 111 pages
File Size : 14,25 MB
Release : 2018-02-19
Category :
ISBN : 2889454223

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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.

Author : Mohit Kumar Jolly
Publisher : MDPI
Page : 512 pages
File Size : 19,70 MB
Release : 2020-12-29
Category : Medical
ISBN : 3039367242

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Recent studies have highlighted that epithelial-mesenchymal transition (EMT) is not only about cell migration and invasion, but it can also govern many other important elements such as immunosuppression, metabolic reprogramming, senescence-associated secretory phenotype (SASP), stem cell properties, therapy resistance, and tumor microenvironment interactions. With the on-going debate about the requirement of EMT for cancer metastasis, an emerging focus on intermediate states of EMT and its reverse process mesenchymal-epithelial transition (MET) offer new ideas for metastatic requirements and the dynamics of EMT/MET during the entire metastatic cascade. Therefore, we would like to initiate discussions on viewing EMT and its downstream signaling networks as a fulcrum of cellular plasticity, and a facilitator of the adaptive responses of cancer cells to distant organ microenvironments and various therapeutic assaults. We hereby invite scientists who have prominently contributed to this field, and whose valuable insights have led to the appreciation of epithelial-mesenchymal plasticity as a more comprehensive mediator of the adaptive response of cancer cells, with huge implications in metastasis, drug resistance, tumor relapse, and patient survival.

Author : Jing Xu
Publisher :
Page : 131 pages
File Size : 12,79 MB
Release : 2019
Category :
ISBN :

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Macroautophagy (hereafter autophagy) is a catabolic cellular process where double-membraned autophagosomes capture cytoplasmic cargos and fuse with lysosomes for content degradation. Basal autophagy maintains cellular homeostasis by removing long-lived proteins and damaged organelles. Autophagy can also be upregulated to promote cell survival in the presence of stressors such as starvation and oxidative stress. Autophagy can suppress tumorigenesis by maintaining genome stability in normal cells, or enable cancer cell survival during nutrient limitation, hypoxia or chemotherapy treatment. Therefore, inhibiting autophagy may improve chemotherapy efficacy. Triple-negative breast cancers (TNBC) are a subtype of breast cancers that do not over-express hormone receptors. Chemotherapy remains one of the few systemic treatment options for TNBC, making the development of chemotherapy resistance particularly problematic in disease management. This thesis describes cell-intrinsic and cell-extrinsic functions of autophagy machinery in cultured TNBC cells, and explores the potential utility of autophagy inhibition to enhance treatment response. Cytoprotective autophagy was induced in response to epirubicin treatment in TNBC cells. Autophagy inhibition reduced cell viability and improved efficacy of epirubicin in both drug-naïve and drug-resistant cells. Further investigation revealed cell-extrinsic roles of autophagy, in the form of its contribution to the composition of small extracellular vesicles (sEV), nano-sized vesicular entities with known roles in cell-cell communication. Lysosomal inhibition by chloroquine (CQ) induced co-localization of mammalian autophagy-related (ATG) 8 homologs with endolysosomal tetraspanins, and introduced significantly higher levels of ATG8s in TNBC-derived sEV. The concurrent increase in poly-ubiquitinated proteins and autophagy adaptors in sEV suggested a potential mechanism where degradative cargos are loaded into sEV by autophagy machinery and then expelled. CQ-induced enrichment of ATGs was limited to a subpopulation of sEV, highlighting the heterogeneity and context-dependency of sEV composition. Finally, CQ-mediated lysosomal inhibition was found to dampen the growth-promoting effects of sEV in recipient cells. Taken together, this work demonstrated cytoprotective roles of autophagy in TNBC cells, and the dynamic contribution of autophagy machinery to sEV composition, warranting further examination of autophagy inhibition as a potential therapeutic avenue in TNBC.

Author : Jin-Ming Yang
Publisher : Springer
Page : 146 pages
File Size : 15,35 MB
Release : 2016-09-02
Category : Medical
ISBN : 3319427407

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This volume will detail the current state and perspectives of autophagy-based cancer therapy. Covering a wide range of topics, it will include an overview of autophagy as a therapeutic target in cancer, autophagy modulators as cancer therapeutic agents, implications of micro-RNA-regulated autophagy in cancer therapy, modulation of autophagy through targeting PI3 kinase in cancer therapy, targeting autophagy in cancer stem cells, and roles of autophagy in cancer immunotherapy. In addition, the volume will review applications of system biology and bioinformatics approaches to discovering cancer therapeutic targets in the autophagy regulatory network. The volume will be beneficial for a variety of basic and clinical scientists, including cancer biologists, autophagy researchers, pharmacologists, and clinical oncologists who wish to delve more deeply into this field of cancer research. This volume will be the first book to focus solely on autophagy as a target in cancer therapy. As well, it will comprehensively discuss the roles of autophagy in most currently available cancer treatments.

Author : Hong-Gang Wang
Publisher : Springer
Page : 0 pages
File Size : 33,14 MB
Release : 2015-02-08
Category : Medical
ISBN : 9781489991775

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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. ​

Author : Doriano Fabbro
Publisher : Springer Science & Business Media
Page : 599 pages
File Size : 32,14 MB
Release : 2007-11-13
Category : Science
ISBN : 1592599621

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Leading researchers, from the Novartis group that pioneered Gleevec/GlivecTM and around the world, comprehensively survey the state of the art in the drug discovery processes (bio- and chemoinformatics, structural biology, profiling, generation of resistance, etc.) aimed at generating PTK inhibitors for the treatment of various diseases, including cancer. Highlights include a discussion of the rationale and the progress made towards generating "selective" low molecular-weight kinase inhibitors; an analysis of the normal function, role in disease, and application of platelet-derived growth factor antagonists; and a summary of the factors involved in successful structure-based drug design. Additional chapters address the advantages and disadvantages of in vivo preclinical models for testing protein kinase inhibitors with antitumor activity and the utility of different methods in the drug discovery and development process for determining "on-target" vs "off-target" effects of kinase inhibitors.