Article

Molecular mechanisms of pancreatic carcinogenesis

Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
Cancer Science (Impact Factor: 3.52). 02/2006; 97(1):1-7. DOI: 10.1111/j.1349-7006.2005.00134.x
Source: PubMed

ABSTRACT

Pancreatic ductal adenocarcinoma is one of the most fatal malignancies. Intensive investigation of molecular pathogenesis might lead to identifying useful molecules for diagnosis and treatment of the disease. Pancreatic ductal adenocarcinoma harbors complicated aberrations of alleles including losses of 1p, 6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic cancer is usually initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate progression of the carcinogenic pathway through pancreatic intraepithelial neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may play suppressive roles in tumorigenesis by inhibition of angiogenesis. Loss of 18q precedes SMAD4 inactivation, and restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, indicating the possible existence of a tumor suppressor gene(s) other than SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanIN, which suggests that DUSP6 works as a tumor suppressor in pancreatic carcinogenesis. Restoration of chromosome 12 also suppresses growths of pancreatic cancer cells despite the recovery of expression of DUSP6; the existence of yet another tumor suppressor gene on 12q is strongly suggested. Understanding the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting, and ultimately curing this life-threatening disease.

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Available from: Toru Furukawa, Oct 11, 2014
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    • "As a result of the cumulative gene mutations which amplify oncogenic signal, aberrant activation of several signaling pathways are observed in pancreatic cancer cells. Up to 95% of pancreatic cancer harbors constitutively active mutation of K-ras oncogene (Furukawa et al., 2006), which leads to the activation of downstream signals for unlimited cellular proliferation. On the other hand, specific gene deletion results in the defect of tumor suppressive signal such as Smad4 deletion, which is observed in 50% of pancreatic cancer (Maitra and Hruban, 2008). "
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    • "Morphologically, PDAC progresses from precursor lesions named " Pancreas Intraepithelial Neoplasias " (PanINs). PanINs show glandular pattern with ductlike structures and varying degrees of cellular atypia and differentiation [19] [20]. They are classified from Grade I, with presence of columnar mucinous epithelium to Grades II and III, with nuclear atypia. "

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