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: 2.14). 01/2001; 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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction: Pancreatic ductal adenocarcinoma is an aggressive tumor; treatment remains a challenge because of the lack of effective therapeutic strategies. Basic research in this field is dependent on the availability of model systems. New pancreatic cancer cell lines are therefore important for the study of its biology. In the present study, we report the establishment and characterization of six new pancreatic cancer cell lines (PaCaDD-). Experimental: All cell lines were derived from pancreatic ductal adenocarcinomas by the Dresden outgrowth protocol. The six cell lines originated from different sample locations. We characterized the cell 22 lines by examining their morphology and their cytostructural and functional profiles. Results and Discussion: All cell lines were cultured in 23 optimized Dresden-Medium. The doubling time ranged from 20 to 43 hours. KRAS mutations were detected in four of the six cell lines. Immunohistochemical staining showed cytoplasmic expression of CK8/18, mostly membrane and partially cytoplasmic expression of E-cadherin and strong expression of ezrin in all cell lines. Three cell lines showed nuclear p53 accumulation and heterogeneous expression of vimentin. SMAD4 was heterogeneously expressed in the cell lines. Conclusions: We were able to establish six new primary pancreatic carcinoma cell lines. As applicable tools for basic research, these cell lines might contribute to a better understanding and treatment of this aggressive tumor.
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: High-resolution, multiphase, computed tomography (CT) is a standard preoperative test prior to pancreatectomy, yet the clinical significance of routinely reported findings remains unknown. METHODS: We identified patients who underwent a pancreaticoduodenectomy for a periampullary adenocarcinoma (PA) over the previous 5 years and had a pancreas protocol CT at our institution. Clinicopathologic implications of reported CT findings were evaluated. RESULTS: There were 155 pancreatic ductal adenocarcinomas (PDA) and 47 non-pancreatic PAs. No mass was visualized on CT in 6 % of PDAs and 23 % of non-pancreatic PA. A size discrepancy of ≥1 cm between radiographic and pathologic tumor diameters was observed in 40 % of PAs, with CT underestimating the size in most instances (75 %). Radiographically enlarged lymph nodes were not associated with true lymph node metastases in PDAs (70 % lymph node positive cases were enlarged on CT vs 74 % lymph node negative, p = 0.5), but were associated with a preoperatively placed biliary endoprosthesis (63 % with endoprosthesis were enlarged vs 37 % no endoprosthesis, p = 0.013). Major visceral vessel involvement on CT was not associated with a vascular resection (3 % with CT vessel involvement vs 2 % without, p = 0.8) or a positive uncinate resection margin (24 vs 20 %, respectively, p = 0.6). DISCUSSION: While dedicated pancreas protocol CT provides unprecedented detail, the test may lead to overinterpretation of the extent of disease in some instances. A radiographic suggestion of enlarged lymph nodes and vascular involvement does not necessarily preclude exploration with curative intent. CTs with local disease should be reported in an objective template and carefully reviewed by a multidisciplinary group of surgeons, radiologists, and oncologists to avoid missing an opportunity for neoadjuvant therapy or cure by resection.
    Journal of Gastrointestinal Surgery 04/2013; · 2.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 01/2012; 7(5):e36719. · 3.53 Impact Factor