Molecular mechanisms of pancreatic carcinogenesis

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.

Figure 1

Aberrations of multiple molecules in pancreatic ductal adenocarcinoma (P). Note loss of expressions of CDKN2A (panel b), SMAD4 (panel d), and DUSP6 (panel e) and abnormal accumulation of TP53 (panel c). Panel a, hematoxylin and eosin staining. N, normal duct.

Figure 2

The RAS‐MAPK pathway with abrogation of DUSP6. Active RAS generated by mutated KRAS activates downstream cascades including RAF1‐MAP2K1‐MAPK1. Loss of expression of DUSP6 results in abrogation of the feedback loop between MAPK1 and DUSP6 and leads to constitutive activation of MAPK1, which eventually results in invasive phenotypes.

Figure 3

Molecular pathways of pancreatic carcinogenesis. Activation of KRAS and SHH along with inactivation of CDKN2A contribute to the formation of low‐grade pancreatic intraepithelial neoplasia (PanIN). Additional inactivation of TP53 and SMAD4 contributes to one step up the carcinogenesis stairs; the tumors turn into high‐grade PanIN. Finally, inactivation of DUSP6 leads to pancreatic ductal adenocarcinoma. PDA, pancreatic ductal adenocarcinoma.