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Arrested development and the great escape - The role of cellular senescence in pancreatic cancer

Lookup NU author(s): John Moir, Steven White, Professor Jelena Mann

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Abstract

The outcomes of pancreatic cancer remain dismal due to late clinical presentation and the aggressive nature of the disease. A heterogeneous combination of genetic mutations, including KRAS, INK4a/CDKN2A and p53, underpin the propensity of pancreatic cancer to rapidly invade and disseminate. These oncogenes and tumour suppressors are strongly associated with cellular senescence, therefore suggesting this process as having a key role in malignant transformation. In the context of cancer, oncogenic stimuli trigger the senescent phenotype resulting in cell cycle growth arrest and prevention of progression of premalignant lesions such as PanINs. However mutations of the aforementioned oncogenes or tumour suppressors result in cells escaping senescence and thus allowing tumours to progress. This review presents current evidence regarding both senescence induction and escape with respect to pancreatic cancer, highlighting the key roles of p19ARF, p53, Rb and P16INK4a. The epigenetic regulatory component is also discussed, with relevance to DNA methylation and HDACs. Lastly the role of the tumour microenvironment, and in particular pancreatic stellate cells, is discussed with regards to the induction of a senescence associated secretory phenotype (SASP), with SASP-associated secretory factors contributing to the pro-tumorigenic effects of the surrounding activated stroma. Further work is required in this field to elucidate the most important pathways relating to cellular senescence that contribute to the belligerent nature of this disease, with the aim of discovering therapeutic targets to improve patient outcomes. (C) 2014 Elsevier Ltd. All rights reserved.


Publication metadata

Author(s): Moir JAG, White SA, Mann J

Publication type: Review

Publication status: Published

Journal: International Journal of Biochemistry & Cell Biology

Year: 2014

Volume: 57

Pages: 142-148

Print publication date: 01/12/2014

Online publication date: 23/10/2014

Acceptance date: 15/10/2014

ISSN (print): 1357-2725

ISSN (electronic): 1878-5875

Publisher: PERGAMON-ELSEVIER SCIENCE LTD

URL: http://dx.doi.org/10.1016/j.biocel.2014.10.018

DOI: 10.1016/j.biocel.2014.10.018


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