Künzli Beat M, Berberat Pascal O, Giese Thomas, Csizmadia Eva, Kaczmarek Elzbieta, Baker Colin, Halaceli Irfan, Büchler Markus W, Friess Helmut, Robson Simon C
Liver and Transplantation Centers, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, 02215, USA.
Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G223-30. doi: 10.1152/ajpgi.00259.2006. Epub 2006 Aug 17.
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 (P2R) in chronic pancreatitis and pancreatic cancer. We have therefore defined tissue distribution and localization of the CD39 family of ectonucleotidases and associated P2R in human disease. Transcripts of ectonucleotidases (CD39 and CD39L1) together with P2R (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.
慢性炎症、纤维化、萎缩、恶性转化和血栓栓塞事件是慢性胰腺疾病的特征。细胞外核苷酸在许多病理情况下被认为是炎症介质。然而，关于外核苷酸酶和2型嘌呤能受体（P2R）在慢性胰腺炎和胰腺癌中表达的详细数据很少。因此，我们确定了人类疾病中外核苷酸酶CD39家族及其相关P2R的组织分布和定位。在慢性胰腺炎和胰腺癌中，外核苷酸酶（CD39和CD39L1）以及P2R（P2X7、P2Y2和P2Y6）的转录本均显著增加。CD39和CD39L1在病理组织中优先与脉管系统和基质成分相关。P2X7 mRNA上调与慢性胰腺炎相关，且发现其蛋白表达增强定位于浸润细胞。P2Y2在胰腺癌组织活检中显著上调，并由肿瘤邻近的成纤维细胞表达。胰腺癌患者肿瘤切除后，CD39的高组织mRNA水平与更好的长期生存率显著相关。CD39、P2X7和P2Y2的表达模式和定位模式增强表明它们与胰腺的慢性炎症和肿瘤形成有关。我们的数据表明，CD39和P2-嘌呤能信号在人类胰腺疾病的组织重塑和纤维化形成中具有不同作用。
