CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Saur
Dieter
D
Department of Internal Medicine 2, Technical University of Munich, Germany. Dieter.Saur@lrz.tu-muenchen.de
Seidler
Barbara
B
Schneider
Günter
G
Algül
Hana
H
Beck
Roswitha
R
Senekowitsch-Schmidtke
Reingard
R
Schwaiger
Markus
M
Schmid
Roland M
RM
D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling / Q000502:physiology; D045744:Cell Line, Tumor; D017931:DNA Primers; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000235:genetics*; D019707:Receptors, Chemokine / Q000235:genetics; D014407:Tumor Cells, Cultured
C515370:CCR7 protein, human; C515371:Ccr7 protein, mouse; D017931:DNA Primers; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine