Expression and Function of CXCR4 in Metastatic Pancreatic Adenocarcinoma
Posted on: Thursday, 17 June 2004, 06:00 CDT
In this study we have evaluated 11 pancreatic tumor cell lines and tumur cells from surgical samples of patients with pancreatic adenocarcinoma for expression of the chemokine receptor CXCR4. Seven of 11 cell lines expressed detectable mRNA transcripts of CXCR4, with three cell lines (AsPC1, Capan1, Hs766T) having substantial amounts of transcripts. Expression was higher in lines derived from metastatic lesions compared to those derived from primary tumors. Different inflammatory cytokines did not modify the expression, while IFNg downregulated and hypoxia upregulated the transcripts in two cell lines tested. All surgical carcinoma samples tested expressed higher levels of CXCR4 than normal pancreatic ducts, used as reference tissue. The chemokine CXCL12 induced chemotaxis in CXCR4-positive pancreatic carcinoma cell lines that was inhibited by anti-CXCR4 mAb and by the compound AMD3100. Transendothelial migration, Matrigel invasion and activation of matrix metalloproteases were also enhanced by CXCLl 2 in these cell lines. Under serum-free conditions, the addition of exogenous CXCL12 inhibited tumor cell death, protecting tumor cells from apoptosis. The cell line HS766T produced high levels of CXCL12. Culture with the inhibitor AMD3100 partially inhibited cell proliferation and, under serum-free conditions, the addition of exogenous CXCL12 restored cell proliferation. Overall these results indicate that CXCR4 receptor is frequently expressed in pancreatic tumor cells. Functional CXCR4 stimulates cell motility and invasion, as well as survival/proliferation. Strategies to target CXCR4 expressed on tumor cells may be of benefit in patients with pancreatic cancer.
F. Marchesi1, P. Monti2, B.E. Leone4, L. Piemonti2, A. Mantovani1,3, P. Allavena1
1Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy; laboratory of Experimental Surgery, Surgical Department, S. Raffaele Scientific Institute, Milan, Italy; 'Institute of Pathology, University of Milan, Milan, Italy; 4Bicocca University of Milan, Milan, Italy
Copyright Edizioni Minerva Medica Mar 2004
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