Submitted on June 13, 2006
Accepted on August 14, 2006
Upregulation of CD39/NTPDases and P2 Receptors in Human Pancreatic Disease
Beat Martin Künzli1, Pascal Oliver Berberat2, Thomas Giese3, Eva Csizmadia1, Elsbieta Kaczmarek1, Colin Baker1, Irfan Halaceli2, Markus W. Buchler4, Helmut Friess2, and Simon C Robson1*
1 Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
2 University of Heidelberg, Department of General Surgery, Heidelberg, Baden-Württemberg, Germany
3 University of Heidelberg, Institute of Immunology, Heidelberg, Baden-Württemberg, Germany
4 University of Heidelberg, Department of General Surgery, United States
* To whom correspondence should be addressed. E-mail: srobson{at}bidmc.harvard.edu.
Chronic inflammation, fibrosis, atrophy, malignant transformation and thromboembolic events are hallmarks of chronic pancreatic disease. Extracellular nucleotides have been implicated as inflammatory mediators in many pathological situations. However, there are minimal data detailing expression of ectonucleotidases and type-2 purinergic receptors (P2-R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2-R in human disease. Transcripts of ectonucleotidases (CD39, CD39L1) together with P2-R (P2X7, P2Y2 and P2Y6) are significantly increased in both chronic pancreatitis and pancreatic cancer. CD39 and CD39L1 are preferentially associated with the vasculature and stromal elements in pathological tissues. P2X7 mRNA upregulation was associated with chronic pancreatitis and heightened protein expression was found to be localized to infiltrating cells. P2Y2 was markedly upregulated in biopsies of pancreatic cancer tissues and expressed by fibroblasts adjacent to tumors. High tissue mRNA levels of CD39 significantly correlated with better long-term survival after tumor resection in patients with pancreatic cancer. Heightened expression patterns and localization patterns of CD39, P2X7 and P2Y2 infer associations with chronic inflammation and neoplasia of the pancreas. Our data suggest distinct roles for CD39 and P2-purinergic signaling in both tissue remodeling and fibrogenesis with respect to human pancreatic diseases.
