Organ-, inflammation- and cancer specific transcriptional fingerprints of pancreatic and hepatic stellate cells.
BACKGROUND
Tissue fibrosis is an integral component of chronic inflammatory (liver and pancreas) diseases and pancreatic cancer. Activated pancreatic- (PSC) and hepatic- (HSC) stellate cells play a key role in fibrogenesis. To identify organ- and disease-specific stellate cell transcriptional fingerprints, we employed genome-wide transcriptional analysis of primary human PSC and HSC isolated from patients with chronic inflammation or cancer.


METHODS
Stellate cells were isolated from patients with pancreatic ductal adenocarcinoma (n = 5), chronic pancreatitis (n = 6), liver cirrhosis (n = 5) and liver metastasis of pancreatic ductal adenocarcinoma (n = 6). Genome-wide transcriptional profiles of stellate cells were generated using our 51K human cDNA microarray platform. The identified organ- and disease specific genes were validated by quantitative RT-PCR, immunoblot, ELISA, immunocytochemistry and immunohistochemistry.


RESULTS
Expression profiling identified 160 organ- and 89 disease- specific stellate cell transcripts. Collagen type 11a1 (COL11A1) was discovered as a novel PSC specific marker with up to 65-fold higher expression levels in PSC compared to HSC (p < 0.0001). Likewise, the expression of the cytokine CCL2 and the cell adhesion molecule VCAM1 were confined to HSC. PBX1 expression levels tend to be increased in inflammatory- vs. tumor- stellate cells. Intriguingly, tyrosine kinase JAK2 and a member of cell contact-mediated communication CELSR3 were found to be selectively up-regulated in tumor stellate cells.


CONCLUSIONS
We identified and validated HSC and PSC specific markers. Moreover, novel target genes of tumor- and inflammation associated stellate cells were discovered. Our data may be instrumental in developing new tailored organ- or disease-specific targeted therapies and stellate cell biomarkers.
Erkan
Mert
M
Department of General Surgery, Technische Universität München, Munich, Germany.
Weis
Nadine
N
Pan
Zheng
Z
Schwager
Christian
C
Samkharadze
Tamar
T
Jiang
Xiaohua
X
Wirkner
Ute
U
Giese
Nathalia A
NA
Ansorge
Wilhelm
W
Debus
Jürgen
J
Huber
Peter E
PE
Friess
Helmut
H
Abdollahi
Amir
A
Kleeff
Jörg
J
D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D016172:DNA Fingerprinting; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D014408:Biomarkers, Tumor