Identifizierung und Validierung von differentiell exprimierten Genen im Stroma von duktalen Pankreaskarzinomen und chronischer Pankreatitis

Abstract

Background: Pancreatic ductal adenocarcinoma is characterized by an abundant desmoplastic stroma. Interactions between cancer and stromal cells play a critical role in tumour invasion, metastasis and chemoresistance. Therefore, we hypothesised that the gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. Methods: We investigated the gene expression of eleven stromal tissue from pancreatic ductal adenocarcinoma, nine from chronic pancreatitis and cell lines of stromal origin using the Affymetrix U133 GeneChip set. The tissue samples were microdissected, the RNA was extracted, amplified, and labelled using a repetitive in vitro transcription protocol. Differentially expressed genes were identified using the significance analysis of microarrays program. Results: We found 255 genes to be over-expressed and 61 genes to be under-expressed within the stroma of pancreatic carcinoma compared to the stroma of chronic pancreatitis. Analysis of the involved signal transduction pathways revealed a number of genes associated with the Wnt pathway. Therefore, we confirmed the differential expression of SFRP1 and WNT5a using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during co-cultivation with a pancreatic carcinoma cell line. Conclusion: The identified differences in the expression profile of stroma cells derived from tumour compared to cells of inflammatory origin suggest a specific response of the tissue surrounding malignant cells. The over-expression of WNT5a, a gene involved in the non canonical Wnt signalling and chondrocyte development might contribute to the strong desmoplastic reaction seen in pancreatic cancer.