Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling

Christian Pilarsky, Ole Ammerpohl, Bence Sipos, Edgar Dahl, Arndt Hartmann, Axel Wellmann, Till Braunschweig, Matthias Löhr, Ralf Jesnowski, Helmut Friess, Moritz Nicolas Wente, Glen Kristiansen, Beatrix Jahnke, Axel Denz, Felix Rückert, Hans K. Schackert, Günter Klöppel, Holger Kalthoff, Hans Detlev Saeger, Robert Grützmann

Research output: Contribution to journalArticlepeer-review

86 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) 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 hypothesized that gene expression profile of the stromal components of pancreatic carcinoma is different from chronic pancreatitis and reflects the interaction with the tumour. We investigated the gene expression of eleven stromal tissues from PDAC, 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 and validated using quantitative RT-PCR and immuno-histochemistry. We found 255 genes to be overexpressed and 61 genes to be underexpressed 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 of which the differential expression of SFRP1 and WNT5a was confirmed using immunohistochemistry. Moreover, we could demonstrate that WNT5a expression was induced in fibroblasts during cocultivation with a pancreatic carcinoma cell line. 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 overexpression 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.

Original languageEnglish
Pages (from-to)2823-2835
Number of pages13
JournalJournal of Cellular and Molecular Medicine
Volume12
Issue number6B
DOIs
StatePublished - Dec 2008
Externally publishedYes

Keywords

  • Chronic pancreatitis
  • Expression profiling
  • Microarray
  • Microdissection
  • Pancreatic ductal adenocarcinoma
  • Stroma
  • WNT5a

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