Article

Molecular pathogenesis of pancreatic ductal adenocarcinoma and clinical implications

University of Liverpool, Department of Surgery, 5th Floor UCD Building, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK.
Surgical Oncology (Impact Factor: 3.27). 07/2001; 10(1-2):1-23. DOI: 10.1016/S0960-7404(01)00016-0
Source: PubMed

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer death worldwide. PDAC is also one of the best-studied cancers with regard to molecular pathogenesis. The chief risk factors associated with PDAC are smoking and pancreatitis, in addition genetic predisposition seems to play a major role. This genetic predisposition may in some cases be indirect, for example via the elevated risk of pancreatitis seen in patients with hereditary pancreatitis (HP). The elucidation of the molecular causes of PDAC has enabled the provision of secondary screening for PDAC in conditions such as HP. This review is concerned with the molecular pathogenesis of PDAC and the application of this basic scientific understanding into state-of-the-art clinical practice.

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    • "Interestingly, treatment of other mouse models of pancreatic cancer, namely KPC-mice, with anti-inflammatory drugs prolonged the time until the development of tumors [43]. Although KRAS mutations are frequently observed in patients with chronic pancreatitis [44], [45], not every patient with pancreatitis and KRAS mutations develop pancreatic cancer [46]. As postulated above, not every inflammatory microenvironment must inevitably result in a feedback loop even if epithelial cells harbor a mutation in a loop gene. "
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    ABSTRACT: The classical somatic mutation theory (SMT) of carcinogenesis and metastasis postulates that malignant transformation occurs in cells that accumulate a sufficient amount of mutations in the appropriate oncogenes and/or tumor suppressor genes. These mutations result in cell-autonomous activation of the mutated cell and a growth advantage relative to neighboring cells. However, the SMT cannot completely explain many characteristics of carcinomas. Contrary to the cell-centered view of the SMT with respect to carcinogenesis, recent research has revealed evidence that the tumor microenvironment plays a role in carcinogenesis as well. In this review, we present a new model that accommodates the role of the tumor microenvironment in carcinogenesis and complements the classical SMT. Our "feedback" model emphasizes the role of an altered spatiotemporal communication between epithelial and stromal cells during carcinogenesis: a dysfunctional intracellular signaling in tumorigenic epithelial cells leads to inappropriate cellular responses to stimuli from associated stromal or inflammatory cells. Thus, a positive feedback loop of the information flow between parenchymal and stromal cells results. This constant communication between the stromal cells and the tumor cells causes a perpetually activated state of tumor cells analogous to resonance disaster.
    Full-text · Article · May 2012 · PLoS ONE
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    • "Pancreas cancer is a most aggressive malignancy with dismal outcome for patients. The disease is usually advanced at presentation (Haycox et al. 1998a) and the aggressive biological phenotype is exceptionally resistant to all forms of therapy (Magee et al. 2001). Surgery offers the only possibility of cure, but even in those curatively resected, the median survival is short (13–18 months) and 5-year survival at best 15–26% (Mosca et al. 1997; Kuhlman et al. 2004; Yeo et al. 1995). "

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    ABSTRACT: Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.
    Full-text · Article · Feb 2002 · Acta Oncologica
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