review of literature on clinical pancreatology - The Pancreapedia

B7 ligand familyB7-H3 is a new member <strong>of</strong> the B7 ligand family and regulates T-cell responses in variousconditions. However, the role <strong>of</strong> B7-H3 in tumour immunity is largely unknown. The purpose<strong>of</strong> one study was to evaluate the clinical significance <strong>of</strong> B7-H3 expression in humanpancreatic cancer and the therapeutic potential for cancer immunotherapy. It wasinvestigated B7-H3 expression in 59 patients with pancreatic cancer byimmunohistochemistry and real-time PCR. Tumour-related B7-H3 expression was abundantin most human pancreatic cancer tissues and was significantly higher compared with that innon-cancer tissue or normal pancreas. Moreover, its expression was significantly moreintense in cases with lymph node metastasis and advanced pathological stage. B7-H3blockade promoted CD8(+) T-cell infiltration into the tumour and induced a substantial antitumoureffect on murine pancreatic cancer. In addition, the combination <strong>of</strong> gemcitabine withB7-H3 blockade showed a synergistic anti-tumour effect without overt toxicity [368].CiliogenesisPrimary cilia have been proposed to participate in the modulation <strong>of</strong> growth factor signalingpathways. In one study, it was determined that ciliogenesis is suppressed in both pancreaticcancer cells and pancreatic intraepithelial neoplasia (PanIN) lesions in human pancreaticductal adenocarcinoma (PDAC). Primary cilia were absent in these cells even when notactively proliferating. Cilia were also absent from mouse PanIN cells in three different mousemodels <strong>of</strong> PDAC driven by an endogenous oncogenic Kras allele. Inhibition <strong>of</strong> Kras effectorpathways restored ciliogenesis in a mouse pancreatic cancer cell line, raising the possibilitythat ciliogenesis may be actively repressed by oncogenic Kras. By contrast, normal duct,islet, and centroacinar cells retained primary cilia in both human and mouse pancreata. Thus,arrested ciliogenesis is a cardinal feature <strong>of</strong> PDAC and its precursor PanIN lesions, does notrequire ongoing proliferation, and could potentially be targeted pharmacologically [369].COX-2Overexpression <strong>of</strong> cyclooxygenase-2 (COX-2) is implicated in cancer development. Onestudy examined the functional relevance <strong>of</strong> genetic polymorphisms in the COX-2 promoterand evaluated their associations with susceptibility to pancreatic cancer. Genotypes andhaplotypes <strong>of</strong> COX-2 -765G/C, -1195G/A, and -1290A/G were analyzed in 393 pancreaticcancer patients and 786 controls. The -1195AA or -765GC genotype carriers had a 1.34-fold(95 % confidence intervall 1.12 to 1.60) or 1.63-fold (95 % confidence intervall 1.25 to 2.10)excess risk for developing pancreatic cancer. These two variants showed a cooperativeeffect in context <strong>of</strong> haplotype, with the odds ratios for the A(-1195)-C(-765)- containinghaplotypes being significantly greater than those for the G(-1195)-G(-765)-containinghaplotypes. The -765C allele and smoking displayed a multiplicative joint effect, with an oddsratio <strong>of</strong> 3.72 (95 % confidence intervall 1.70to 8.14) for heavy smokers carrying the -765GCgenotype. Biochemical assays suggest that the -765GC change creates a binding site fornucleophosmin (NPM) and phosphorylated NPM (p-NPM), which acts as a transcriptionalinhibitor. Cigarette smoke remarkably increased COX-2 promoter activity, and this effect wasmore pronounced for the -765C allele compared with the -765G allele. Cigarette smokereduced nuclear p-NPM levels, which was reversely associated with COX-2 expression. Itwas thus found that functional COX-2 polymorphisms are associated with susceptibility topancreatic cancer and tobacco smoke specifically increases -765C promoter activity, whichmight be mediated by p-NPM [370].