Overlapping and distinct role of CXCR7-SDF-1/ITAC and CXCR4-SDF-1 axes in regulating metastatic behavior of human rhabdomyosarcomas.
We have demonstrated that the α-chemokine stromal-derived factor (SDF)-1-CXCR4 axis plays an important role in rhabdomyosarcoma (RMS) metastasis. With the recent description of CXCR7, a new receptor for SDF-1 that also binds the interferon-inducible T-cell α chemoattractant (ITAC) chemokine, we became interested in the role of the CXCR7-SDF-1/ITAC axis in RMS progression. To address this issue, we evaluated 6 highly metastatic alveolar (A)RMS and 3 less metastatic embryonal (E)RMS cell lines and found that all these cell lines express CXCR7. Although CXCR4 was expressed at a much higher level by highly metastatic ARMS lines, CXCR7 was present at a high level on ERMS lines. We also noticed that CXCR7 expression on RMS cells was downregulated in hypoxic conditions. More importantly, the CXCR7 receptor on RMS cell lines was functional after stimulation with ITAC and SDF-1 as evidenced by mitogen-activated protein kinase (MAPK)p42/44 and AKT phosphorylation as well as CXCR7 internalization, chemotaxis, cell motility and adhesion assays. Similarly to CXCR4, signaling from activated CXCR7 was not associated with increased RMS proliferation or cell survival. Moreover, CXCR7(+) RMS cells responded to SDF-1 and I-TAC in the presence of CXCR4 antagonists (T140, AMD3100). Furthermore, while intravenous injection of RMS cells with overexpressed CXCR7 resulted in increased seeding efficiency of tumor cells to bone marrow, CXCR7 downregulation showed the opposite effect. In conclusion, the CXCR7-SDF-1/ITAC axis is involved in the progression of RMS; targeting of the CXCR4-SDF-1 axis alone without simultaneous blockage of CXCR7 will be an inefficient strategy for inhibiting SDF-1-mediated prometastatic responses of RMS cells.
Grymula
Katarzyna
K
Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
Tarnowski
Maciej
M
Wysoczynski
Marcin
M
Drukala
Justyna
J
Barr
Frederic G
FG
Ratajczak
Janina
J
Kucia
Magdalena
M
Ratajczak
Mariusz Z
MZ
D000818:Animals; D001596:Benzylamines; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054371:Chemokine CXCL11 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D015536:Down-Regulation; D042783:Endothelial Cells / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009842:Oligopeptides / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation; D054387:Receptors, CXCR / Q000096:biosynthesis / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018232:Rhabdomyosarcoma, Alveolar / Q000378:metabolism* / Q000473:pathology; D018233:Rhabdomyosarcoma, Embryonal / Q000378:metabolism* / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism
C501896:ACKR3 protein, human; D001596:Benzylamines; C515202:CXCL11 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054371:Chemokine CXCL11; D054377:Chemokine CXCL12; D000080027:Cyclams; D005353:Fibronectins; D006571:Heterocyclic Compounds; D009842:Oligopeptides; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; D019714:Tissue Inhibitor of Metalloproteinases; C116977:T140 peptide; D037342:Pertussis Toxin; D020782:Matrix Metalloproteinases; C088327:plerixafor