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


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.
    PLoS ONE 05/2012; 7(5):e36719. DOI:10.1371/journal.pone.0036719 · 3.23 Impact Factor
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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: Arachidonic acid metabolites known to affect platelet function also interfere with tumor growth and metastases. The purpose of this study was to evaluate the anti-metastatic potential of ketoconazole, a thromboxane synthetase and 5-lipoxygenase inhibitor, on hepatic metastasis from a human pancreatic adenocarcinoma in nude mice and its effect on serum prostaglandin levels. The human pancreatic tumor cells (RWP-2) were injected intrasplenically in nude mice grouped into control, ketoconazole (270 microg), ketoconazole (360 microg), and ketoconazole (540 microg). The agent was administered intraperitoneally 30 min before and every 24 h after the tumor cell inoculation for 8 days. In a separate experiment thromboxane B2 (TxB2), prostaglandin D2 (PGD2), prostaglandin E2 (PGE2) and 6-Keto-F1a (stable prostacyclin derivative) were measured on blood from controls, tumor bearing animals and animals bearing tumors treated with 270 microg of ketoconazole. Statistically significant differences were observed between the control and three-treatment groups on the reduction of liver tumor nodules (p < 0.001), and in the liver surface areas occupied by tumor (p < 0.001). The TxB2 levels decreased from 150.6 ng/mL in the tumor bearing to 104.8 ng/mL in the ketoconazole treated animals (p < 0.05). PGD2, PGE2 and 6-keto-F1a levels increased to 7.1 ng/mL, 8.3 ng/mL, and 13.6 ng/mL from 3 ng/mL, 5.8 ng/mL, and 0.02 ng/mL respectively (p < 0.001). These results indicate that ketoconazole significantly reduced hepatic metastases from the human pancreatic carcinoma RWP-2 in the nude mouse model, and inhibited thromboxane B2 formation, potentiating a concomitant redirection of platelet endoperoxide metabolism into PGD2, PGE2, and 6-keto-F1a. It is hypothesized that the changes in the arachidonic acid metabolism mediate the ameliorating effect of ketoconazole on experimental hepatic metastasis.
    International Journal of Gastrointestinal Cancer 01/2002; 32(1):23-30. DOI:10.1385/IJGC:32:1:23
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