Mechanisms involved in the differential bone marrow homing of CD45 subsets in 5T murine models of myeloma
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Multiple myeloma (MM) is an incurable plasma cell cancer, localized in the bone marrow (BM). The mechanisms used by these cells to (re-)enter this organ remain largely unknown. Recently, we reported that both CD45+ and CD45− myeloma cells home to the BM and induce myeloma disease. In this work, we investigated the underlying mechanisms involved in the homing of CD45+ and CD45− myeloma cells in the experimental 5T2MM and 5T33MM murine models. In vivo tracing of flow cytometric sorted and radioactively labeled CD45 subsets revealed a reduced homing of the CD45− 5TMM cells to the BM as compared to the CD45+ 5TMM cells. Migration assays demonstrated an impaired chemotaxis towards BM endothelial cell conditioned medium, BM stromal cell conditioned medium and towards the basement membrane component laminin-1 of the CD45− 5TMM cells compared to the CD45+ subset. Matrix metalloproteinase-9 (MMP-9) and urokinase type plasminogen activator (uPA) are key extracellular matrix proteases involved in the invasion of cancer cells. Inhibitor and antibody blocking experiments demonstrated the involvement of both in the invasion of the 5TMM cells. CD45− 5TMM cells had a low secretion of MMP-9 and (for the non-aggressive line 5T2MM only) a low cell surface expression of uPA receptor, as revealed by gelatin zymography and flow cytometric analysis, respectively. Accordingly, the synthetic basement membrane invasive capacity of the CD45− 5TMM subpopulations was also impaired. Our results indicate that CD45+ and CD45− 5T myeloma cells have a differential BM homing attributable to differential migratory and invasive capacities.
- Vanderkerken K, De Greef C, Asosingh K et al. Selective initial in vivo homing pattern of 5T2 multiple myeloma cells in the C57BL/KalwRij mouse. Br J Cancer 2000; 82: 953–59. CrossRef
- Butcher EC, Picker LJ. Lymphocyte homing and homeostasis. Science 1996; 272: 60–6.
- Vanderkerken K, Asosingh K, Braet F et al. Insulin-like growth factor-1 acts as a chemoattractant factor for 5T2 multiple myeloma cells. Blood 1999; 93: 235–41.
- Asosingh K, Gunthert U, Bakkus MH et al. In vivo induction of insulin-like growth factor-I receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells. Cancer Res 2000; 60: 3096–104.
- Asosingh K, Gunthert U, De Raeve H et al. A unique pathway in the homing of murine multiple myeloma cells: CD44v10 mediates binding to bone marrow endothelium. Cancer Res 2001; 61: 2862–5.
- Asosingh K, Radl J, Van Riet I et al. The 5TMM series: A useful in vivo mouse model of human multiple myeloma. Hematol J 2000; 1: 351–6. CrossRef
- Radl J, De Glopper ED, Schuit HR et al. Idiopathic paraproteinemia. II. Transplantation of the paraprotein-producing clone from old to young C57BL/KaLwRij mice. J Immunol 1979; 122: 609–13.
- Radl J, Croese JW, Zurcher C et al. Animal model of human disease. Multiple myeloma. Am J Pathol 1988; 132: 593–7.
- Vanderkerken K, De Raeve H, Goes E et al. Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL/KaLwRij mouse. Br J Cancer 1997; 76: 451–60.
- Van Valckenborgh E, De Raeve H, Devy L et al. Murine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo. Br J Cancer 2002; 86: 796–802. CrossRef
- Jensen GS, Poppema S, Mant MJ et al. Transition in CD45 isoform expression during differentiation of normal and abnormal B cells. Int Immunol 1989; 1: 229–36.
- Asosingh K, De Raeve H, Croucher P et al. In vivo homing and differentiation characteristics of mature (CD45−) and immature (CD45+) 5T multiple myeloma cells. Exp Hematol 2001; 29: 77–84. CrossRef
- Gardsvoll H, Solberg H, Dano K et al. Generation of high-affinity rabbit polyclonal antibodies to the murine urokinase receptor using DNA immunization. J Immunol Methods 2000; 234: 107–16. CrossRef
- Garbisa S, Sartor L, Biggin S et al. Tumor gelatinases and invasion inhibited by the green tea flavanol epigallocatechin-3-gallate. Cancer 2001; 91: 822–32. CrossRef
- Vanderkerken K, Vande Broek I, Eizerik DL et al. Monocyte chemoattractant-1 (MCP-1), secreted by bone marrow endothelial cells, induces chemoattraction of multiple myeloma cells. Clin Exp Metastasis 2002; 19: 87–90. CrossRef
- Vracko R. Basal lamina scaffold-anatomy and significance for maintenance of orderly tissue structure. Am J Pathol 1974; 77: 314–46.
- Vande Broek I, Vanderkerken K, De Greef C et al. The high affinity 67 kD laminin receptor is expressed by multiple myeloma cells and mediates cell migration. Br J Cancer 2002; 85: 1387–95. CrossRef
- Stetler-Stevenson WG, Liotta LA, Kleiner DE, Jr. Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. Faseb J 1993; 7: 1434–41.
- Noel A, Gilles C, Bajou K et al. Emerging roles for proteinases in cancer. Invasion Metastasis 1997; 17: 221–39.
- Liotta LA, Tryggvason K, Garbisa S et al. Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 1980; 284: 67–8. CrossRef
- Liotta LA. Tumor invasion and metastases-role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res 1986; 46: 1–7. CrossRef
- Nykjaer A, Conese M, Christensen EI et al. Recycling of the urokinase receptor upon internalization of the uPA:serpin complexes. Embo J 1997; 16: 2610–20. CrossRef
- Hjertner O, Qvigstad G, Hjorth-Hansen H et al. Expression of urokinase plasminogen activator and the urokinase plasminogen activator receptor in myeloma cells. Br J Haematol 2000; 109: 815–22. CrossRef
- Dhodapkar M V Sanderson RD. Syndecan-1 (CD 138) in myeloma and lymphoid malignancies: A multifunctional regulator of cell behavior within the tumor microenvironment. Leuk Lymph 1999; 34: 35–43.
- Himelstein BP., Canete-Soler R, Bernhard EJ et al. Metalloproteinases in tumor progression: the contribution of MMP-9. Invasion Metastasis 1994; 14: 246–58.
- John A, Tuszynski G. The role of matrix metalloproteinases in tumor angiogenesis and tumor metastasis. Pathol Oncol Res 2001; 7: 14–23. CrossRef
- Vanderkerken K, Van Valckenborg E, Bakkus M et al. Bone marrow microenvironmental-induced upregulation of MMP-9 activity in murine multiple myeloma cells. Clin Exp Metastasis 2000; 17: 766 (abstract).
- Vacca A, Ribatti D, Presta M et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999; 93: 3064–73.
- Barillé S, Bataille R, Rapp MJ et al. Production of metalloproteinase-7 (matrilysin) by human myeloma cells and its potential involvement in metalloproteinase-2 activation. J Immunol 1999; 163: 5723–8.
- Kaushal GP, Xiong X, Athota AB et al. Syndecan-1 expression suppresses the level of myeloma matrix metalloproteinase-9. Br J Haematol 1999; 104: 365–73. CrossRef
- Mechanisms involved in the differential bone marrow homing of CD45 subsets in 5T murine models of myeloma
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