Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma

Abstract

Pancreatic fibrosis (PF) is an essential component of the pathobiology of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC). Activated pancreatic myofibroblasts (PMFs) are crucial for the deposition of the extracellular matrix, and fibrotic reaction in response to sustained signaling. Consequently, understanding of the molecular mechanisms of PMF activation is not only critical for understanding CP and PDAC biology but is also a fertile area of research for the development of novel therapeutic strategies for pancreatic pathologies. This review analyzes the key signaling events that drive PMF activation including, initiating signals from transforming growth factor-β1, platelet derived growth factor, as well as other microenvironmental cues, like hypoxia and extracellular matrix rigidity. Further, we discussed the intracellular signal events contributing to PMF activation, and crosstalk with different components of tumor microenvironment. Additionally, association of epidemiologically established risk factors for CP and PDAC, like alcohol intake, tobacco exposure, and metabolic factors with PMF activation, is discussed to comprehend the role of lifestyle factors on pancreatic pathologies. Overall, this analysis provides insight into the biology of PMF activation and highlights salient features of this process, which offer promising therapeutic targets.

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Acknowledgements

The authors/work, in parts, were supported by the NIH grants (F30 CA225117, R21CA223429, R21 AA026428, R44 CA235991, P01 CA217798, Great Plains IDeA-CTR, R01 CA183459, R01 CA210637, and R01 CA228524), and the University of Nebraska Collaboration Initiative/System Science Seed Grant (20063).

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Correspondence to Sushil Kumar or Surinder Kumar Batra.

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SKB is one of the co-founders of the Sanguine Diagnostics and Therapeutics, Inc. The other authors declare no competing interests.

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Cannon, A., Thompson, C.M., Bhatia, R. et al. Molecular mechanisms of pancreatic myofibroblast activation in chronic pancreatitis and pancreatic ductal adenocarcinoma. J Gastroenterol 56, 689–703 (2021). https://doi.org/10.1007/s00535-021-01800-4

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Keywords

  • Pancreatic fibrosis
  • Chronic pancreatitis
  • Pancreatic cancer
  • Myofibroblast
  • Cell signaling