Molecular pathogenesis of pancreatic ductal adenocarcinoma and clinical implications.
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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ABSTRACT: Transforming growth factor (TGF)-beta signaling is initiated by heterodimerization of TGF-beta receptor type I (TbetaRI) and type II (TbetaRII). Subsequently, the signal is transduced via Smad proteins, which upon phosphorylation and heterodimerization translocate to the nucleus and regulate gene transcription. Smad6 functions as an intracellular antagonist of TGF-beta signaling. In the present study we demonstrate that Smad6 is overexpressed in vivo in human pancreatic cancer cells. We also show that stable transfection of a full-length Smad6 construct into COLO-357 pancreatic cancer cells abrogates TGF-beta1 induced growth inhibition, and leads to enhanced anchorage-independent growth. Thus, enhanced expression of the TGF-beta signaling inhibitor Smad6 in pancreatic cancer may present a novel mechanism of TGF-beta resistance, which might have the potential to enhance the transformed phenotype of human cancer cells.Biochemical and Biophysical Research Communications 03/1999; 255(2):268-73. · 2.41 Impact Factor
- Cell 08/2000; 102(1):9-15. · 31.96 Impact Factor
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ABSTRACT: We have reported the presence of c-K-ras oncogenes activated by single point mutations at codon 12 in a vast majority of human pancreatic carcinomas. Formalin-fixed, paraffin-embedded specimens from surgical resections, autopsies and biopsies were used as well as snap frozen surgical specimens. The high oncogene incidence has been confirmed in other studies and indicate that somatic mutational activation of the c-K-ras gene is an important event in the development, maintenance or progression of cancer of the exocrine pancreas. While the role that these point mutations play in any or all of these processes remains to be determined, their presence is useful clinically for the diagnosis of pancreatic carcinoma at the molecular genetic level. The detection of mutated c-K-ras oncogenes in fine needle aspirates of pancreatic masses, that by cytomorphology may be suspicious but not diagnostic of malignant disease, increases the sensitivity of the diagnosis for this cancer. The identification of codon 12 mutations in the c-K-ras gene in pancreatic adenocarcinomas has been possible by advances in recombinant DNA techniques, especially by the development of in vitro gene amplification by the polymerase chain reaction (PCR). The possibility of analysing formalin-fixed, paraffin-embedded tissue for the presence of genetic alterations as small as single point mutations by PCR in concert with other mutation detection techniques, should facilitate the molecular genetic analysis of pancreatic carcinoma. Retrospective studies using stored specimens are now feasible with the technology described and should yield important information on the molecular epidemiology and aetiology of this and other diseases.Baillière s Clinical Gastroenterology 04/1990; 4(1):151-69.