CXCR4 Expression Increases Liver and Lung Metastasis in a Mouse Model of Pancreatic Cancer

转移 胰腺癌 CXCR4型 癌症研究 CXCR4拮抗剂 趋化因子受体 C-C趋化因子受体7型 医学 体内 癌症 趋化因子 病理 胰腺肿瘤 生物 受体 内科学 生物技术
作者
Dieter Saur,Barbara Seidler,Günter Schneider,Hana Algül,Roswitha Beck,Reingard Senekowitsch–Schmidtke,Markus Schwaiger,Roland M. Schmid
出处
期刊:Gastroenterology [Elsevier BV]
卷期号:129 (4): 1237-1250 被引量:180
标识
DOI:10.1053/j.gastro.2005.06.056
摘要

Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion, and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ-specific pancreatic cancer metastasis in vivo remains unclear. Here, we have studied the role of CXCR4 in vivo using noninvasive imaging of targeted metastasis in a mouse model of pancreatic cancer.Functional expression of the chemokine receptors CXCR4 and CCR7 was achieved by stable transfection of murine TD-2 pancreatic cancer cells and analyzed by flow cytometry, calcium flux, migration, and proliferation assays. The metastatic potential of the different stable TD-2 cell clones was assessed by tail vein metastatic assays in nude mice using in vivo bioluminescent imaging.Native TD-2 cells display very low abundant CXCR4 and CCR7 expression and show poor metastatic potential after tail vein injection. To study the role of CXCR4 in pancreatic cancer metastasis, we selected stable TD-2 cell clones with similar CXCR4 expression levels as human pancreatic cancer cell lines derived from metastatic lesions. CXCR4, but not CCR7, expression dramatically increased the in vivo metastatic potential of TD-2 cells, resulting in liver and lung metastasis in nude mice. Systemic administration of the selective CXCR4 inhibitor AMD 3100 effectively blocked the enhanced metastatic potential of CXCR4-expressing pancreatic cancer cells.These results indicate that CXCR4 expression mediates organ-specific metastasis of pancreatic cancer cells and provide preclinical evidence that blockade of the CXCL12/CXCR4 axis is a target for antimetastatic therapy.
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