Pancreatitis-Induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced Senescence

Despite many years of effort from cancer biologists and clinical oncologists, pancreatic ductal adenocarcinoma (PDAC) remains a thoroughly recalcitrant disease, resisting both conventional forms of cancer treatment and radical innovative therapies. Perhaps driving the lack of success in PDAC is the underappreciation of the primary hallmark of the tumour: a fibrotic extracellular matrix (ECM) that composes a majority of the highly rigid solid carcinoma. In recent years we have come to understand that the homeostasis of ECM mechanics is pivotal for the homeostasis of cells and the progression or initiation of a malignant phenotype. This can be understood by way of mechanobiology, a field that attempts to understand how physical forces like ECM stiffness alter cell behaviour. In this review, we provide an overview of our understanding of PDAC from this perspective and the recent advances in biophysics and engineering that allow for new tools with which to investigate the mechanobiology of PDAC.

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“…TP53) or pre-existing inflammation (e.g. repeated bouts of pancreatitis) that are usually required for invasive PDAC to develop [26].…”

Section: Mechanical Forces Play Key Role In Pdacmentioning

confidence: 99%

Pancreatic cancer: a mechanobiology approach

Chronopoulos

Lieberthal

Hernández

2017

Converg. Sci. Phys. Oncol.

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“…Therefore, we expect new development in prevention and therapeutic methods by understanding the process of aging. (65) Cellular senescence, as one basic process that play most contribution to age-related dysfunction and chronic sterile inflammation, refers to the essentially irreversible growth arrest that occurs when cells experience potentially oncogenic insults (58,(130)(131)(132)(133)(134), and now believe that it was the potent anticancer mechanism (135)(136)(137)(138). In contrast, despite its name, its discovery over 50 years ago, and increasing data associating senescent cells with aging phenotypes and age-related pathology (59,(139)(140)(141)(142)(143)(144)(145), while eliminating senescent cells could delay age-related dysfunction (146), at least in a progeroid mouse model.…”

Section: Telomeres and Diseasesmentioning

confidence: 99%

Telomere in Aging and Age-Related Diseases

2017

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B ACKGROUND:The number of elderly population in the world keep increasing. In their advanced ages, many elderly face years of disability because of multiple chronic diseases, frailty, making them lost their independence. Consequently, this could have impacts on social and economic stability. A huge challenge has been sent for biomedical researchers to compress or at least eliminate this period of disability and increase the health span. CONTENT:Over the past decades, many studies of telomere biology have demonstrated that telomeres and telomere-associated proteins are implicated in human diseases. Accelerated telomere erosion was clearly correlated with a pack of metabolic and inflammatory diseases. Critically short telomeres or the unprotected end, are likely to form telomeric fusion, generating genomic Abstract R E V I E W A R T I C L Einstability, the cornerstone for carcinogenesis. Enlightening how telomeres involved in the mechanisms underlying the diseases' pathogenesis was expected to uncover new molecular targets for any important diagnosis or therapeutic implications. SUMMARY:Telomere shortening was foreseen as an imporant mechanism to supress tumor by limiting cellular proliferative capacity by regulating senescence check point activation. Many human diseases and carcinogenesis are causally related to defective telomeres, asserting the importance of telomeres sustainment. Thus, telomere length assessment might serve as an important tool for clinical prognostic, diagnostic, monitoring and management.

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“…Notably, the latent period and penetrance of PanIN lesion development are similar to those expressing the KRAS G12D oncogene. The above model enables expression of KRAS oncogene to be activated in a controlled temporal manner by feeding the mice with doxycycline (52).…”

Section: Mouse Modelmentioning

confidence: 99%

Critical role of oncogenic KRAS in pancreatic cancer (Review)

Liu

Liang

et al. 2016

Molecular Medicine Reports

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Abstract. Pancreatic cancer is a human malignancy with one of the highest mortality rates and little progress has been achieved in its treatment in recent decades. Further improvement to the understanding of the biological and molecular mechanisms underlying the initiation and development of pancreatic ductal adenocarcinoma (PDAC) is required. Previous studies using genetically engineered mouse models have demonstrated that oncogenic GTPase KRas (KRAS) mutation is involved in the formation of pancreatic intraepithelial neoplasia and promotes the progression of PDAC. However, attempts to target KRAS directly by pharmacological inhibition have been unsuccessful. This has resulted in increased efforts to identify pharmacological targets and nodes associated with the mutated KRAS. The present review discusses the recent progress and prospects of KRAS signaling in pancreatic cancer. IntroductionPancreatic ductal adenocarcinoma (PDAC) is an incurable disease that results in mortality. The number of newly diagnosed cases almost equals the annual number of deaths despite advances in surgery and chemoradiotherapy in the past decades. Although the 5-year survival of pancreatic cancer patients has almost doubled over the past decade, it remains low at ~7-8% according to the US National Cancer Institute (1). A lack of early diagnostic strategies, high resistance to chemoradiotherapy and early local or distant metastatic recurrence following surgery are the three predominant factors that contribute to poor outcomes. Further understanding of the biological and molecular mechanisms underlying the initiation and development of PDAC are required. Genetically, cancer progresses as a result of the combined activation of oncogenes and inactivation of tumor suppressors. Similarly, numerous molecular alterations are also required for pancreatic intraepithelial neoplasias (PanIN) lesions to develop into PDAC. Previous studies have established that PDAC is characterized by four signature mutations including mutations in GTPase KRas (KRAS) oncogene and in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), and SMAD family member 4 (SMAD4) tumor suppressor genes (2,3). Approximately 90% of pancreatic neoplasms express mutant KRAS, which has been hypothesized to be the initiator of PDAC. However, the development of therapeutic agents targeting KRAS in PDAC remains unsuccessful. The present review discusses recent research regarding KRAS and explores potential therapeutic targets. InitiationPDAC develops with progressive cellular, morphological and architectural changes from normal ductal epithelium to preneoplastic lesions, and then PanINs and PDAC. The majority of PDAC and early PanIN lesions involve mutations in the KRAS oncogene. Almoguera et al (4) and Smit et al (5) first established the association between the mutant KRAS gene and PDAC in 1988. To investigate the role of the KRAS oncogene in the onset of PDAC, multiple genetically engineered mouse (GEM) models were established. The first model was the endogen...

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Pancreatitis-Induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced Senescence

Cited by 464 publications

References 36 publications

Pancreatic cancer: a mechanobiology approach

Pancreatic cancer: a mechanobiology approach

Telomere in Aging and Age-Related Diseases

Critical role of oncogenic KRAS in pancreatic cancer (Review)

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