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Clinical & Experimental Metastasis

, Volume 23, Issue 5–6, pp 291–300 | Cite as

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

  • Eline MenuEmail author
  • Evy De Leenheer
  • Hendrik De Raeve
  • Les Coulton
  • Takeshi Imanishi
  • Kazuyuki Miyashita
  • Els Van Valckenborgh
  • Ivan Van Riet
  • Ben Van Camp
  • Richard Horuk
  • Peter Croucher
  • Karin Vanderkerken
Original Paper

Abstract

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 1α (MIP1α) could be detected by ELISA. In vitro migration assays showed that MIP1α 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.

Keywords

Chemokines Homing Myeloma Osteolysis Therapy 

Notes

Acknowledgments

We would like to thank C. Seynaeve, A. Willems, L. Moeneclaey, G. Vrolix, O. Gallagher, M. Prideaux and F. Rylant for technical assistance and the lab of Prof. Gorus (AZ VUB, Brussels) for serum paraprotein analysis. We would also like to thank Dr. Fujiwara for providing TAK779.

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Copyright information

© Springer Science + Business Media B.V. 2006

Authors and Affiliations

  • Eline Menu
    • 1
    Email author
  • Evy De Leenheer
    • 2
  • Hendrik De Raeve
    • 3
  • Les Coulton
    • 2
  • Takeshi Imanishi
    • 4
  • Kazuyuki Miyashita
    • 4
  • Els Van Valckenborgh
    • 1
  • Ivan Van Riet
    • 1
  • Ben Van Camp
    • 1
  • Richard Horuk
    • 5
  • Peter Croucher
    • 2
  • Karin Vanderkerken
    • 1
  1. 1.Department of Hematology and ImmunologyVrije Universiteit Brussel-VUBBrusselsBelgium
  2. 2.Division of Clinical Sciences (South)University of Sheffield, Medical SchoolSheffieldUK
  3. 3.Department of PathologyUniversity of AntwerpAntwerpBelgium
  4. 4.Bioorganic & Organic Chemistry, Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan
  5. 5.Department of ImmunologyBerlex BiosciencesCaliforniaUSA

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