The involvement of the fractalkine receptor in the transmigration of neuroblastoma cells through bone-marrow endothelial cells.
Transendothelial migration (TEM) of tumor cells is a crucial step in metastasis formation. The prevailing paradigm is that the mechanism underlying TEM of tumor cells is similar to that of leukocytes involving adhesion molecules and chemokines. Fractalkine (CX3CL1) is a unique membrane-bound chemokine that functions also as an adhesion molecule. CX3CL1 can be cleaved to a soluble fragment, capable of attracting fractalkine receptor (CX3CR1)-expressing cells. In the present study, we asked if CX3CR1 is involved in the TEM of neuroblastoma cells. We demonstrated that biologically functional CX3CR1 is expressed by several neuroblastoma cell lines. Most importantly, CX3CR1-expressing neuroblastoma cells were stimulated by CX3CL1 to transmigrate through human bone-marrow endothelial cells. A dose dependent phosphorylation of ERK1/2 and AKT was induced in CX3CR1-expressing neuroblastoma cells by soluble CX3CL1. In addition to CX3CR1, neuroblastoma cells also express the CX3CL1 ligand. Membrane CX3CL1 expression was downregulated and the shedding of soluble CX3CL1 was upregulated by PKC activation. Taken together, the results of this study indicate that CX3CR1 plays a functional role in transmigration of neuroblastoma cells through bone-marrow endothelium. These results led us to hypothesize that the CX3CR1-CX3CL1 axis takes part in bone-marrow metastasis of neuroblastoma.
Nevo
Ido
I
Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
Sagi-Assif
Orit
O
Meshel
Tsipi
T
Ben-Baruch
Adit
A
Jöhrer
Karin
K
Greil
Richard
R
Trejo
Leonor E Leider
LE
Kharenko
Oleg
O
Feinmesser
Meora
M
Yron
Ilana
I
Witz
Isaac P
IP
D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology*; D000073883:CX3C Chemokine Receptor 1; D045744:Cell Line, Tumor; D002465:Cell Movement; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology*; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009447:Neuroblastoma / Q000503:physiopathology*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; C095235:CX3CR1 protein, human; D054428:Chemokine CX3CL1; D019707:Receptors, Chemokine; D051058:Oncogene Protein v-akt; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases