Role of CCR1 and CCR5 in homing and growth of multiple myeloma and in the development of osteolytic lesions: a study in the 5TMM model.
Multiple myeloma (MM) is a plasma cell malignancy, characterized by the localization of the MM cells in the bone marrow (BM), where they proliferate and induce osteolysis. The MM cells first need to home or migrate to the BM to receive necessary survival signals. In this work, we studied the role of CCR1 and CCR5, two known chemokine receptors, in both chemotaxis and osteolysis in the experimental 5TMM mouse model. A CCR1-specific (BX471) and a CCR5-specific (TAK779) antagonist were used to identify the function of both receptors. We could detect by RT-PCR and flow cytometric analyses the expression of both CCR1 and CCR5 on the cells and their major ligand, macrophage inflammatory protein 1alpha (MIP1alpha) could be detected by ELISA. In vitro migration assays showed that MIP1alpha induced a 2-fold increase in migration of 5TMM cells, which could only be blocked by TAK779. In vivo homing kinetics showed a 30% inhibition in BM homing when 5TMM cells were pre-treated with TAK779. We found, in vitro, that both inhibitors were able to reduce osteoclastogenesis and osteoclastic resorption. In vivo end-term treatment of 5T2MM mice with BX471 resulted in a reduction of the osteolytic lesions by 40%; while TAK779 treatment led to a 20% decrease in lesions. Furthermore, assessment of the microvessel density demonstrated a role for both receptors in MM induced angiogenesis. These data demonstrate the differential role of CCR1 and CCR5 in MM chemotaxis and MM associated osteolysis and angiogenesis.
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Eline
E
Department of Hematology and Immunology, Vrije Universiteit Brussel-VUB, Laarbeeklaan 103, 1090 Brussels, Belgium, Eline.Menu@vub.ac.be
De Leenheer
Evy
E
De Raeve
Hendrik
H
Coulton
Les
L
Imanishi
Takeshi
T
Miyashita
Kazuyuki
K
Van Valckenborgh
Els
E
Van Riet
Ivan
I
Van Camp
Ben
B
Horuk
Richard
R
Croucher
Peter
P
Vanderkerken
Karin
K
D000577:Amides / Q000494:pharmacology; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D001862:Bone Resorption / Q000188:drug therapy; D065100:CCR5 Receptor Antagonists; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000494:pharmacology / Q000502:physiology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009101:Multiple Myeloma / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D010010:Osteoclasts / Q000502:physiology; D010014:Osteolysis / Q000209:etiology / Q000503:physiopathology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D054389:Receptors, CCR1; D019713:Receptors, CCR5 / Q000502:physiology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D017154:Stromal Cells / Q000187:drug effects; D047368:Tumor Burden
D000577:Amides; D065100:CCR5 Receptor Antagonists; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins; C119369:TAK 779; C411885:BX 471