Skip to main content

Advertisement

SpringerLink
Log in

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

  • Original Paper
  • Published:
Clinical & Experimental Metastasis Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Bakkus MH, Heirman C, Van Riet I et al (1992) Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 80:2326–2335

    PubMed  CAS  Google Scholar 

  2. Caligaris-Cappio F, Bergui L, Gregoretti MG et al (1991) Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77:2688–2693

    PubMed  CAS  Google Scholar 

  3. Lokhorst HM, Lamme T, de Smet M et al (1994) Primary tumor cells of myeloma patients induce interleukin-6 secretion in long-term bone marrow cultures. Blood 84:2269–2277

    PubMed  CAS  Google Scholar 

  4. Uchiyama H, Barut BA, Mohrbacher AF et al (1993) Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82:3712–3720

    PubMed  CAS  Google Scholar 

  5. Van Riet I, Van Camp B (1993) The involvement of adhesion molecules in the biology of multiple myeloma. Leuk Lymphoma 9:441–452

    Article  PubMed  Google Scholar 

  6. Butcher EC, Picker LJ (1996) Lymphocyte homing and homeostasis. Science 272:60–66

    Article  PubMed  CAS  Google Scholar 

  7. Tanaka T, Bai Z, Srinoulprasert Y et al (2005) Chemokines in tumor progression and metastasis. Cancer Sci 96:317–322

    Article  PubMed  CAS  Google Scholar 

  8. Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115

    Article  PubMed  CAS  Google Scholar 

  9. Olson TS, Ley K (2002) Chemokines and chemokine receptors in leukocyte trafficking. Am J Physiol Regul Integr Comp Physiol 283:R7–R28

    PubMed  CAS  Google Scholar 

  10. Menten P, Wuyts A, Van Damme J (2002) Macrophage inflammatory protein-1. Cytokine Growth Factor Rev 13:455–481

    Article  PubMed  CAS  Google Scholar 

  11. Schall TJ, Bacon K, Camp RD et al (1993) Human macrophage inflammatory protein alpha (MIP-1 alpha) and MIP-1 beta chemokines attract distinct populations of lymphocytes. J Exp Med 177:1821–1826

    Article  PubMed  CAS  Google Scholar 

  12. Lentzsch S, Gries M, Janz M et al (2003) Macrophage inflammatory protein 1-alpha (MIP-1 alpha) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 101:3568–3573

    Article  PubMed  CAS  Google Scholar 

  13. Choi SJ, Cruz JC, Craig F et al (2000) Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. Blood 96:671–675

    PubMed  CAS  Google Scholar 

  14. Han JH, Choi SJ, Kurihara N et al (2001) Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 97:3349–3353

    Article  PubMed  CAS  Google Scholar 

  15. Choi SJ, Oba Y, Gazitt Y et al (2001) Antisense inhibition of macrophage inflammatory protein 1-alpha blocks bone destruction in a model of myeloma bone disease. J Clin Invest 108:1833–1841

    Article  PubMed  CAS  Google Scholar 

  16. Abe M, Hiura K, Wilde J et al (2002) Role for macrophage inflammatory protein (MIP)-1alpha and MIP-1beta in the development of osteolytic lesions in multiple myeloma. Blood 100:2195–2202

    PubMed  CAS  Google Scholar 

  17. Fuller K, Owens JM, Chambers TJ (1995) Macrophage inflammatory protein-1 alpha and IL-8 stimulate the motility but suppress the resorption of isolated rat osteoclasts. J Immunol 154:6065–6072

    PubMed  CAS  Google Scholar 

  18. Kukita T, Nomiyama H, Ohmoto Y et al (1997) Macrophage inflammatory protein-1 alpha (LD78) expressed in human bone marrow: its role in regulation of hematopoiesis and osteoclast recruitment. Lab Invest 76:399–406

    PubMed  CAS  Google Scholar 

  19. Oyajobi BO, Franchin G, Williams PJ et al (2003) Dual effects of macrophage inflammatory protein-1alpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood 102:311–319

    Article  PubMed  CAS  Google Scholar 

  20. Roodman GD, Choi SJ (2004) MIP-1 alpha and myeloma bone disease. Cancer Treat Res 118:83–100

    PubMed  CAS  Google Scholar 

  21. Terpos E, Politou M, Rahemtulla A (2003) New insights into the pathophysiology and management of bone disease in multiple myeloma. Br J Haematol 123:758–769

    Article  PubMed  CAS  Google Scholar 

  22. Radl J, De Glopper E, Schuit HRE et al (1979) Idiopathic paraproteinemia II. Transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J Immunol 122:609–613

    PubMed  CAS  Google Scholar 

  23. Vanderkerken K, De Greef C, Asosingh K et al (2000) Selective initial in vivo homing pattern of 5T2 multiple myeloma cells in the C57BL/KalwRij mouse. Br J Cancer 82:953–959

    Article  PubMed  CAS  Google Scholar 

  24. Vanderkerken K, De Raeve H, Goes E et al (1997) Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer 76:451–460

    PubMed  CAS  Google Scholar 

  25. Asosingh K, Radl J, Van Riet I et al (2000) The 5TMM series, a useful in vivo mouse model of human multiple myeloma. Hematol J 1:351–356

    Article  PubMed  CAS  Google Scholar 

  26. Vanderkerken K, Asosingh K, Croucher P et al ( 2003) Multiple myeloma biology: lessons from the 5TMM models. Immunol Rev 194:196–206

    Article  PubMed  CAS  Google Scholar 

  27. Liang M, Mallari C, Rosser M et al (2000) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275:19000–19008

    Article  PubMed  CAS  Google Scholar 

  28. Baba M, Nishimura O, Kanzaki N et al (1999) A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc Natl Acad Sci USA 96:5698–5703

    Article  PubMed  CAS  Google Scholar 

  29. Van Valckenborgh E, De Raeve H, Devy L et al (2002) Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo. Br J Cancer 86:796–802

    Article  PubMed  Google Scholar 

  30. Croucher PI, Shipman CM, Lippitt J et al (2001) Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma. Blood 98:3534–3540

    Article  PubMed  CAS  Google Scholar 

  31. Terpos E, Politou M, Szydlo R et al (2003) Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma. Br J Haematol 123:106–109

    Article  PubMed  CAS  Google Scholar 

  32. Hashimoto T, Abe M, Oshima T et al (2004). Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma. Br J Haematol 125:38–41

    Article  PubMed  CAS  Google Scholar 

  33. Menu E, Asosingh K, Van Riet I et al (2004) Myeloma cells (5TMM) and their interactions with the marrow microenvironment. Blood Cells Mol Dis 33:111–119

    Article  PubMed  Google Scholar 

  34. Menu E, Asosingh K, Indraccolo S et al (2006) The involvement of stromal derived factor 1alpha in homing and progression of multiple myeloma in the 5TMM model. Haematologica 91:605–612

    PubMed  CAS  Google Scholar 

  35. Oba Y, Lee JW, Ehrlich LA et al (2005) MIP-1alpha utilizes both CCR1 and CCR5 to induce osteoclast formation and increase adhesion of myeloma cells to marrow stromal cells. Exp Hematol 33:272–278

    Article  PubMed  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Department of Hematology and Immunology, Vrije Universiteit Brussel-VUB, Laarbeeklaan 103, 1090 , Brussels, Belgium

    Eline Menu, Els Van Valckenborgh, Ivan Van Riet, Ben Van Camp & Karin Vanderkerken

  2. Division of Clinical Sciences (South), University of Sheffield, Medical School, Sheffield, UK

    Evy De Leenheer, Les Coulton & Peter Croucher

  3. Department of Pathology, University of Antwerp, Antwerp, Belgium

    Hendrik De Raeve

  4. Bioorganic & Organic Chemistry, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    Takeshi Imanishi & Kazuyuki Miyashita

  5. Department of Immunology, Berlex Biosciences, California, USA

    Richard Horuk

Authors
  1. Eline Menu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Evy De Leenheer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hendrik De Raeve
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Les Coulton
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takeshi Imanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kazuyuki Miyashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Els Van Valckenborgh
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ivan Van Riet
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ben Van Camp
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard Horuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Croucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Karin Vanderkerken
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eline Menu.

Additional information

Research Grant Support: The work was financially supported by senior MMRF grants (K. Vanderkerken, P. Croucher), the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (FWO-Vl), the Belgische Federatie tegen Kanker and the Onderzoeksraad Vrije Universiteit Brussel (OZR-VUB). K. Vanderkerken is a postdoctoral fellow of FWO-Vl. P. Croucher is supported by the Leukemia Research Fund and E. Menu by the van der Schueren award.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Menu, E., De Leenheer, E., De Raeve, H. et al. 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. Clin Exp Metastasis 23, 291–300 (2006). https://doi.org/10.1007/s10585-006-9038-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-006-9038-6

Keywords

Search

Navigation