Molecular mechanism of parenchymal injury and the role of duct obstruction and ductal hypertension in the pathogenesis of chronic pancreatitis

The pathobiology of chronic pancreatitis (CP) remains enigmatic despite remarkable progress made recently in uncovering key mechanisms involved in the initiation and progression of the disease. CP is increasingly thought of as a multifactorial disorder. Apoptosis plays a role in parenchymal destruction, the pathological hallmark of CP. The apoptotic mechanisms preferentially target the exocrine compartment, leaving endocrine islets relatively intact for a prolonged period. Exocrine cells shed their "immunoprivileged" status, express death receptors, and are rendered susceptible to apoptosis induced by death ligands on infiltrating lymphocytes, and released locally by activated pancreatic stellate cells. Islet cells retain their "immunoprivileged" status and activate anti-apoptotic programs through NF-kappaB. Ductal changes, including distortion, dilatation, and pancreatic ductal hypertension in the setting of CP, induce genomic damage and increased cell turnover. In addition, signaling mechanisms that play a role in the development of embryonic pancreas are reinstated, thus, playing a role in repair, regeneration, and transformation. This, in turn, leads to acino-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN). Some of these pathways are activated in pancreatic cancer. We attempt to integrate the current knowledge and major concepts in the pathogenesis of CP and to explain the mechanism of differential cell loss. We outline the possible implications of signaling pathway activation in pancreatic inflammation, relevant to the cellular transformation that may cause transformation leading to pancreatic neoplasia

Tumoral Intraductal Neoplasms of the Bile Ducts Comprise Morphologically and Genetically Distinct Entities

CONTEXT.—Tumoral (grossly visible) intraductal neoplasms of the bile ducts are still being characterized. OBJECTIVE.—To investigate their morphologic, immunohistochemical, and molecular features. DESIGN.—Forty-one cases were classified as gastric-, intestinal-, pancreatobiliary-type intraductal papillary neoplasm (IPN), intraductal oncocytic papillary neoplasm (IOPN), or intraductal tubulopapillary neoplasm (ITPN) on the basis of histology. All neoplasms were subjected to targeted next-generation sequencing. RESULTS.—The mean age at diagnosis was 69 years (42-81 years); male to female ratio was 1.3. Most neoplasms (n = 23, 56%) were extrahepatic/large (mean size, 4.6 cm). The majority (n = 32, 78%) contained high-grade dysplasia, and 68% (n = 28) revealed invasion. All gastric-type IPNs (n = 9) and most ITPNs/IOPNs showed consistent colabeling for CK7/MUC6, which was less common among others (P = .004). Intestinal-type IPNs (n = 5) showed higher rates of CK20 expression than others (P < .001). Overall, the most commonly mutated genes included TP53 and APC, while copy number variants affected ELF3 and CDKN2A/B. All gastric-type IPNs contained an alteration affecting the Wnt signaling pathway; 7 of 9 (78%) showed aberrations in the MAPK pathway. Mutations in APC and KRAS were common in gastric-type IPNs as compared with others (P = .01 for both). SMAD4 was more frequently mutated in intestinal-type IPNs (P = .02). Pancreatobiliary-type IPNs (n = 14) exhibited frequent alterations in tumor suppressor genes including TP53, CDKN2A/B, and ARID2 (P = .04, P = .01 and P = .002, respectively). Of 6 IOPNs analyzed, 3 (50%) revealed ATP1B1-PRKACB fusion. ITPNs (n = 6) showed relatively few recurrent genetic aberrations. Follow-up information was available for 38 patients (median, 58.5 months). The ratio of disease-related deaths was higher for the cases with invasion (56% versus 10%). CONCLUSIONS.—Tumoral intraductal neoplasms of the bile ducts, similar to their counterparts in the pancreas, are morphologically and genetically heterogeneous

NF-κB Regulates Androgen Receptor Expression and Prostate Cancer Growth

Prostate cancers that progress during androgen-deprivation therapy often overexpress the androgen receptor (AR) and depend on AR signaling for growth. In most cases, increased AR expression occurs without gene amplification and may be due to altered transcriptional regulation. The transcription factor nuclear factor (NF)-κB, which is implicated in tumorigenesis, functions as an important downstream substrate of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, AKT, and protein kinase C and plays a role in other cancer-associated signaling pathways. NF-κB is an important determinant of prostate cancer clinical biology, and therefore we investigated its role in the regulation of AR expression. We found that NF-κB expression in prostate cancer cells significantly increased AR mRNA and protein levels, AR transactivation activity, serum prostate-specific antigen levels, and cell proliferation. NF-κB inhibitors decrease AR expression levels, prostate-specific antigen secretion, and proliferation of prostate cancer cells in vitro. Furthermore, inhibitors of NF-κB demonstrated anti-tumor activity in androgen deprivation-resistant prostate cancer xenografts. In addition, levels of both NF-κB and AR were strongly correlated in human prostate cancer. Our data suggest that NF-κB can regulate AR expression in prostate cancer and that NF-κB inhibitors may have therapeutic potential