Activation of Wnt signalling in stroma from pancreatic cancer identified by gene expression profiling.
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.
Pilarsky
Christian
C
Department of Visceral-, Thoracic- and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Dresden, Germany. christian.pilarsky@mailbox.tu-dresden.de
Ammerpohl
Ole
O
Sipos
Bence
B
Dahl
Edgar
E
Hartmann
Arndt
A
Wellmann
Axel
A
Braunschweig
Till
T
Löhr
Matthias
M
Jesenofsky
Ralf
R
Jesnowski
Ralf
R
Friess
Helmut
H
Wente
Moritz Nicolas
MN
Kristiansen
Glen
G
Jahnke
Beatrix
B
Denz
Axel
A
Rückert
Felix
F
Schackert
Hans K
HK
Klöppel
Günter
G
Kalthoff
Holger
H
Saeger
Hans Detlev
HD
Grützmann
Robert
R
D045744:Cell Line, Tumor; D016000:Cluster Analysis; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism*
D051153:Wnt Proteins