The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia
- 29 July 2008
- Vol. 57 (11), 1555-1560
- https://doi.org/10.1136/gut.2007.143941
Abstract
Objective: The chemokine CXCL12, together with its specific receptor, CXCR4, have been shown to mediate invasiveness and metastatic behaviour in pancreatic cancer cells. The expression of CXC12/CXCR4 has not been previously examined in pancreatic intraepithelial neoplasias (PanIN), the accepted precursor lesions to pancreatic duct cancer. Design: In this study we sought to characterise the expression of CXCL12 and CXCR4 during the progression of PanIN using both a murine model and human tissues. Results: These studies reveal that both CXCL12 and CXCR4 are expressed in PanIN and that the frequency increases during PanIN progression (0% CXCR4 expression in normal mouse and human ducts vs 100% in mouse PanIN 3 and 77% in human PanIN 3). Next we demonstrate a dose-dependent increase in the proliferation of murine PanIN cells when exposed to CXCL12. Finally, we show that expression of CXCR4 in murine PanIN cells is partially dependent on mitogen-activated protein kinase (MAPK) signalling and that the effect of CXCL12 on PanIN proliferation can be abrogated by an MAPK inhibitor. Conclusions: Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.Keywords
This publication has 25 references indexed in Scilit:
- Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic CancerCell Stem Cell, 2007
- The RON Receptor Tyrosine Kinase Mediates Oncogenic Phenotypes in Pancreatic Cancer Cells and Is Increasingly Expressed during Pancreatic Cancer ProgressionCancer Research, 2007
- Functions of CXCL12 and CXCR4 in breast cancerCancer Letters, 2006
- Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4British Journal of Cancer, 2006
- Regulation of CXCR4-Mediated Nuclear Translocation of Extracellular Signal-Related Kinases 1 and 2Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) ,2005
- CXCR4 Expression Increases Liver and Lung Metastasis in a Mouse Model of Pancreatic CancerGastroenterology, 2005
- Chemokines in tumor progression and metastasisCancer Science, 2005
- The α-Chemokine, Stromal Cell-derived Factor-1α, Binds to the Transmembrane G-protein-coupled CXCR-4 Receptor and Activates Multiple Signal Transduction PathwaysJournal of Biological Chemistry, 1998
- Integration of MAP Kinase Signal Transduction Pathways at the Serum Response ElementScience, 1995
- Maximal activation of transcription by statl and stat3 requires both tyrosine and serine phosphorylationCell, 1995