Chemokine receptor CXCR4-beta1 integrin axis mediates tumorigenesis of osteosarcoma HOS cells.
It is known that beta1 integrins mediate the migratory response of cells to chemokine stimulation. Also, both beta1 integrins and chemokines have roles in tumor development. In the present study, the beta1 integrin-chemokine axis is assessed using human osteosarcoma (HOS) transfectant cells expressing the CXCR4 receptor for chemokine SDF-1 (CXCL12). We first identified in vitro the specific beta1 integrins that mediated the migratory response to SDF-1 stimulation. Results showed that on collagen type I and laminin, the chemotactic response to SDF-1 was predominantly mediated by alpha2beta1 integrin. On fibronectin, SDF-1-stimulated chemotaxis involved both alpha4beta1 and alpha5beta1 integrins. A comparison of the transfectant clones expressing CXCR4 at low, intermediate, and high levels and the control transfectant revealed that the transfectant clones migratory response in vitro and their ability to form tumors in vivo was related to their levels of CXCR4 expression. In addition, treatment by injection with mAbs to CXCR4, integrin alpha2beta1, or integrin alpha5beta1 effectively inhibited the growth of HOS-CXCR4 transfectant cells in vivo. Therefore, our results show that the beta1 integrins that mediated the migratory response were also functionally linked to the enhanced tumor growth of CXCR4-expressing HOS transfectant cells.
Miura
Kohei
K
Biotherapeutics Research Group, Robarts Research Institute and Department of Microbiology and Immunology, University of Western Ontario, London, ON N6A 5K8, Canada.
Uniyal
Shashi
S
Leabu
Mircea
M
Oravecz
Tamas
T
Chakrabarti
Subrata
S
Morris
Vincent L
VL
Chan
Bosco M C
BM
D000818:Animals; D000911:Antibodies, Monoclonal; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D012516:Osteosarcoma / Q000378:metabolism* / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D000911:Antibodies, Monoclonal; D019012:Integrin beta1; D019718:Receptors, CXCR4