HER-family gene amplification and expression in resected pancreatic cancer.

AIMS: Despite surgical resection, pancreatic cancer carries a poor prognosis. In search for new molecular therapeutic targets, we investigated the expression of the HER-family and gene amplification of HER-2 in pancreatic adenocarcinomas of different stages. METHODS: Tissue of 45 resected patients was analyzed for all HER-family 1-4 expression by immunohistochemistry and HER-2 gene amplification was assessed by multiplex ligation-dependent probe amplification and chromogenic in situ hybridization. The type of surgery, location, stage and grade of the tumor, as well as involvement of the resection margins were correlated with HER-expressions and univariate and multivariate survival analysis performed. RESULTS: Normal pancreatic tissue lacked HER1-2 expression, but did show HER3-4 expression. In cancers, no membranous overexpression of HER-1 and HER-2 was seen nor gene amplification of HER-2 found. HER-3, HER-4 is physiologically expressed in the normal pancreas and loss of cytoplasmic HER-3 and HER-4 expression was seen in 33/45 (73%) and 8/45 (18%) of pancreatic cancers. Cytoplasmic HER-3 expression decreased from early to late stage (p=0.05). HER-4 expression was not associated with survival, stage or tumor grade. There were no statistically significant differences in HER1-4 expression between the papilla of Vater (n=13) and non-papilla cancers (n=32). Multivariate survival analysis showed only stage to be of independent prognostic value (p=0.015). CONCLUSIONS: HER-1 and HER-2 are not overexpressed in pancreatic cancers. HER-3 and HER-4 are expressed in the normal pancreas but expression is lost in pancreatic cancer. HER-targeted therapy in pancreatic cancer is not supported by HER-expression of the tumor.

Distribution of cellular prion protein in normal human cerebral cortex--does it have relevance to Creutzfeldt-Jakob disease?

Creutzfeldt-Jakob disease and bovine spongiform encephalopathy are the best known forms of prion diseases. A basis for their pathogenesis is the transformation of normal prion protein to abnormal prion protein. This would mean that either loss of normal function or a gain of a toxic function of the prion protein would play a major role. Since the prime target for Creutzfeldt-Jakob disease in humans is the neocortex, and the intracortical distribution of the destructive process in prion diseases appears not to be haphazard, it may be that a clear cortical study of normal prion protein production in the premorbid human neocortex might contribute to insight in the pathogenesis of prion diseases. As no such study is available, we performed a detailed study in normal human cortex using immunohistochemistry for prion protein, in both frozen and vibratomised tissue, and in situ hybridisation for prion protein mRNA. We have found normal prion protein production mainly in the upper cortical neurons in neocortex and Purkinje cells in the cerebellum. This finding implicates that normal prion protein is more important as an anti-apoptotic signal in disease than abnormal prion protein is as a toxic substance.