Abstract
Pancreatic cancer (PC) is an aggressive type of cancer with poor prognosis and survivability, ranking fourth in the USA and eighth worldwide. Several factors like reactive oxygen species (ROS), extracellular matrix (ECM), cytokines, growth factors, and vasoactive stimuli were shown to be involved in the development of PC. These ROS are generated through the activation of NADPH oxidase (NOX), a multi-subunit enzyme. ROS play an important role in cellular processes like proliferation, migration, differentiation, cell signaling cascade, and the development of immunity. NOX is localized in the membrane and cytosol and gets activated by several environmental stress, growth factors, chemical factors, and vasoactive stimuli like endothelins (ETs). This enzyme complex modulates ROS, causing cellular stress and various lethal disease conditions including PC. In PC, ROS levels are higher compared to healthy condition. Depending upon the concentration, ROS plays dual roles in PC. Different PC cell lines highly express the ET-axis components (ETs, receptors, and ET-converting enzymes) compared to normal cells. ETs mediate their effect through dual receptors, ETAR and ETBR. Endothelin-1 (ET-1) is the most potent vasoconstrictor of ETs and also acts as a vibrant regulator for PC and other cancers. ET axis exerts its effects on PC tumor microenvironment by stimulating ROS production, modulates the immune system, and causes invasion, migration, and proliferation. Herein, we described the role of ROS and ET axis in the PC tumor microenvironment and provide an overview of pathophysiological aspects of the pancreas and the future therapy for PC.
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Abbreviations
- AM:
-
adrenomedullin
- CTGF:
-
connective tissue growth factor
- DBTC:
-
dibutyltin dichloride
- EMMPRIN:
-
ECM metalloproteinase inducer
- IL:
-
interleukin
- IGF:
-
insulin-like growth factor
- MAPK:
-
mitogen-activated protein kinase
- MMPs:
-
matrix metalloproteinases
- NADPH:
-
nicotinamide adenine dinucleotide phosphate
- PKC:
-
protein kinase C
- PI3K:
-
phosphoinositide 3-kinase
- PLD:
-
phospholipase D
- SDF:
-
stromal cell-derived factor
- SPARC:
-
secreted protein acidic and rich in cysteine
- TIMPs:
-
tissue inhibitors of metalloproteinases
- TNF:
-
tumor necrosis factor
- TSP:
-
thrombospondin
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This work was supported in part by National Institutes of Health grants R01AR068279 (NIAMS), STTR R42EY031196 (NEI), and STTR 1R41AG057242 (NIA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Sarkar, J., Das, H. (2022). The Role of Endothelin Axis and Reactive Oxygen Species in Future Therapies of Pancreatic Cancer. In: Chakraborti, S. (eds) Handbook of Oxidative Stress in Cancer: Therapeutic Aspects. Springer, Singapore. https://doi.org/10.1007/978-981-16-1247-3_272-1
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