review of literature on clinical pancreatology - The Pancreapedia

Annexin A5Protein misfolding is a central mechanism for the development <strong>of</strong> neurodegenerativediseases and type 2 diabetes mellitus. The accumulation <strong>of</strong> misfolded alpha-synucleinprotein inclusions in the Lewy bodies <strong>of</strong> Parkinson's disease is thought to play a key role inpathogenesis and disease progression. Similarly, the misfolding <strong>of</strong> the beta-cell hormonehuman islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in theinduction <strong>of</strong> beta-cell apoptosis in the context <strong>of</strong> type 2 diabetes. In one study, it was shownthat annexin A5 plays a role in interacting with and reducing the toxicity <strong>of</strong> the amyloidogenicproteins, h-IAPP and alpha-synuclein. It was found that annexin A5 is coexpressed in humanbeta-cells and that exogenous annexin A5 reduces the level <strong>of</strong> h-IAPP-induced apoptosis inhuman islets by approximately 50 protein and in rodent beta-cells by approximately 90protein. Experiments with transgenic expression <strong>of</strong> alpha-synuclein in Caenorhabditiselegans show that annexin A5 reduces alpha-synuclein inclusions in vivo. Using thi<strong>of</strong>lavin Tfluorescence, electron microscopy, and electron paramagnetic resonance, it was providedevidence that substoichiometric amounts <strong>of</strong> annexin A5 inhibit h-IAPP and alpha-synucleinmisfolding and fibril formation. It was concluded that annexin A5 might act as a molecularsafeguard against the formation <strong>of</strong> toxic amyloid aggregates [365].Basement membrane proteinsThe pathogenesis <strong>of</strong> pancreatic carcinoma is driven by the tumor cells ability to migratecausing invasion and metastases. The correlation between the aberrant expression <strong>of</strong>basement membrane proteins and the process <strong>of</strong> tumor invasion and metastasis has notbeen fully determined. In one study, the influence <strong>of</strong> laminin, fibronectin, and collagen type IVon migratory activity <strong>of</strong> 5 different cell lines has been investigated at the level <strong>of</strong> a singletumor cell using 3-dimensional time-lapse microscopy. All investigated cell lines have showna high baseline migration. The addition <strong>of</strong> laminin, fibronectin, and collagen type IV tocollagen type I matrix has significantly increased tumor cell migration. Tumor cell migrationwas strongly inhibited after treating the tumor cells with anti-beta1 monoclonal antibodies. Anabundant and continuous expression <strong>of</strong> laminin, fibronectin, and collagen type IV was foundon the basement membrane <strong>of</strong> perineurium, which sharply promoted tumor cell invasion. Theauthors concluded that continuous presentation <strong>of</strong> the basement membrane proteins byperineurium contributes to the affinity <strong>of</strong> pancreatic cancer cells for the perineural tumorinvasion. Blockade <strong>of</strong> integrins could represent a possible approach to control the basementmembrane-guided tumor spread [366].BCRA1Available studies allow to estimate that genetic factors play a role in 5-10 percent <strong>of</strong> patientswith pancreatic cancer. Beside other carcinomas, pancreatic cancer occurs in hereditaryneoplastic syndromes associated with gene mutations, including CDKN2A, CHEK2, BRCA2.It has also been suggested that BRCA1 mutation is involved given the fact that BRCA1mutation carriers are at increased risk for pancreatic cancer. However, a role <strong>of</strong> this mutationis not fully understood. Eighty-eight pancreatic cancer patients (56 males and 35 females)and 3784 carriers <strong>of</strong> BRCA1 mutation from 1637 families were enrolled in the study. Almost65 percent <strong>of</strong> pancreatic cancer patients were cigarette smokers. Genotyping for constitutiveBRCA1 gene mutation was performed in all patients with pancreatic cancer. ASA-PCR andPCR-RFLP methods were used to detect BRCA1 (5382insC, C61G, 4153delA) mutations.The frequency <strong>of</strong> pancreatic cancer in families <strong>of</strong> BRCA1 mutation carriers was evaluated.No carriers <strong>of</strong> BRCA1 mutation were identified in patients with pancreatic cancer. Only in 11families (0.7 %) with BRCA1 mutation carriers, pancreatic cancer was diagnosed. The resultssuggest that there is no relationship between BRCA1 mutation and pancreatic cancerdevelopment in Polish population [367].