Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms

Leukemia volume 17, pages 1175–1182 (2003)Cite this article

Abstract

The tumor microenvironment plays a critical role in determining the fate of tumor cells. We have previously reported that adhesion of human myeloma and leukemia cell lines to the extracellular matrix protein, fibronectin, confers a multidrug-resistant phenotype. Mechanisms associated with this cell adhesion-mediated drug resistance are drug-type specific. In the present study, we examined the influence of bone marrow stromal cells (BMSCs) on myeloma cell response to the topoisomerase II inhibitor, mitoxantrone. Apoptosis was inhibited by more than 50% when cells were adhered to BMSCs as compared to myeloma cells maintained in suspension. To investigate the mechanisms contributing to the resistance of myeloma cells in contact with BMSCs, we examined the protective effects of BMSCs under four separate conditions: (1) direct cell contact; (2) BMSCs conditioned medium; (3) medium conditioned by coculturing myeloma cells in direct contact with BMSCs; and (4) medium conditioned by coculturing myeloma cells and BMSCs without direct physical contact. Conditioned medium from BMSCs alone was not sufficient to protect myeloma cells from drug-induced apoptosis; however, soluble factors produced during the myeloma-BMSCs interaction decreased the sensitivity of myeloma cells to mitoxantrone, suggesting a dynamic interaction between myeloma cells and BMSCs. We also found that myeloma cells in direct contact with BMSCs underwent growth arrest, whereas soluble factors produced by myeloma cells-BMSCs coincubation stimulated the proliferation of myeloma cells. These data show that both cell–cell adhesion of BMSCs with myeloma cells and soluble factors induced by this cell–cell interaction are involved in the protection of myeloma cells from mitoxantrone-induced apoptosis; however, the mechanisms contributing to the drug resistance are different.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Dalton WS . Mechanisms of drug resistance in hematologic malignancies. Semin Hematol 1997; 34: 3–8.

    CAS  PubMed  Google Scholar 

  2. Sonneveld P, Lokhorst HM, Vossebeld P . Drug resistance in multiple myeloma. Semin Hematol 1997; 34(Suppl 5): 34–39.

    CAS  PubMed  Google Scholar 

  3. Shain KH, Dalton WS . Cell adhesion is a key determinant in de novo multidrug resistance (MDR): new targets for the prevention of acquired MDR. Mol Cancer Ther 2001; 1: 69–78.

    CAS  PubMed  Google Scholar 

  4. Damiano JS, Dalton WS . Integrin-mediated drug resistance in multiple myeloma. Leukemia and Lymphoma 2000; 38: 71–81.

    Article  CAS  PubMed  Google Scholar 

  5. Shain KH, Landowski TH, Dalton WS . The tumor microenvironment as a determinant of cancer cell survival: a possible mechanism for de novo drug resistance. Curr Opin Oncol 2000; 12: 557–563.

    Article  CAS  PubMed  Google Scholar 

  6. Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med 1999; 5: 662–667.

    Article  CAS  PubMed  Google Scholar 

  7. Garrido SM, Appelbaum FR, Willman CL, Banker DE . Acute myeloid leukemia cells are protected from spontaneous and drug-induced apoptosis by direct contact with a human bone marrow stromal cell line (HS-5). Exp Hematol 2001; 29: 448–457.

    Article  CAS  PubMed  Google Scholar 

  8. Mudry RE, Fortney JE, York T, Hall BM, Gibson LF . Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood 2000; 96: 1926–1932.

    CAS  PubMed  Google Scholar 

  9. Cheung WC, Van Ness B . The bone marrow stromal microenvironment influences myeloma therapeutic response in vitro. Leukemia 2001; 15: 264–271.

    Article  CAS  PubMed  Google Scholar 

  10. Nachbaur DM, Herold M, Maneschg A, Huber H . Serum levels of interleukin-6 in multiple myeloma and other hematological disorders: correlation with disease activity and other prognostic parameters. Ann Hematol 1991; 62: 54–58.

    Article  CAS  PubMed  Google Scholar 

  11. Di Raimondo F, Azzaro MP, Palumbo G, Bagnato S, Giustolisi G, Floridia P et al. Angiogenic factors in multiple myeloma: higher levels in bone marrow than in peripheral blood. Haematologica 2000; 85: 800–805.

    CAS  PubMed  Google Scholar 

  12. Bataille R, Jourdan M, Zhang XG, Klein B . Serum levels of interleukin 6, a potent myeloma cell growth factor as a reflect, of disease severity in plasma cell dyscrasias. J Clin Invest 1989; 84: 2008–2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R et al. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999; 93: 3064–3073.

    CAS  PubMed  Google Scholar 

  14. Zhang XG, Bataille R, Widjenes J, Klein B . Interleukin-6 dependence of advanced malignant plasma cell dyscrasias. Cancer 1992; 69: 1373–1376.

    Article  CAS  PubMed  Google Scholar 

  15. Ruoslahti E, Reed JC . Anchorage dependence integrins and apoptosis. Cell 2000; 77: 477–478.

    Article  Google Scholar 

  16. Scott G, Cassidy L, Busacco A . Fibronectin suppresses apoptosis in normal human melanocytes through an integrin-dependent mechanism. J Invest Dermatol 1997; 108: 147–153.

    Article  CAS  PubMed  Google Scholar 

  17. de la Fuente MT, Casanova B, Moyano JV, Garcia-Gila M, Sanz L, Garcia-Marco J et al. Engagement of alpha4beta1 integrin by fibronectin induces in vitro resistance of B chronic lymphocytic leukemia cells to fludarabine. J Leukocyte Biol 2002; 71: 495–502.

    CAS  PubMed  Google Scholar 

  18. Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood 1999; 93: 1658–1667.

    CAS  PubMed  Google Scholar 

  19. Hazlehurst LA, Damiano JS, Buyuksal I, Pledger WJ, Dalton WS . Adhesion to fibronectin via beta1 integrins regulates p27kip1 levels and contributes to cell adhesion mediated drug resistance (CAM-DR). Oncogene 2000; 19: 4319–4327.

    Article  CAS  PubMed  Google Scholar 

  20. Shain KH, Landowski TH, Dalton WS . Adhesion-mediated intracellular redistribution of c-Fas-associated death domain-like IL-1-converting enzyme-like inhibitory protein-long confers resistance to CD95-induced apoptosis in hematopoietic cancer cell lines. J Immunol 2002; 168: 2544–2553.

    Article  CAS  PubMed  Google Scholar 

  21. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P . Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998; 91: 2387–2396.

    CAS  PubMed  Google Scholar 

  22. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000; 95: 2630–2636.

    CAS  PubMed  Google Scholar 

  23. Oshiro MM, Landowski TH, Catlett-Falcone R, Hazlehurst LA, Huang M, Jove R et al. Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells. Clin Cancer Res 2001; 7: 4262–4271.

    CAS  PubMed  Google Scholar 

  24. Damiano JS, Hazlehurst LA, Dalton WS . Cell adhesion-mediated drug resistance (CAM-DR) protects the K562 chronic myelogenous leukemia cell line from apoptosis induced by BCR/ABL inhibition, cytotoxic drugs, and gamma-irradiation. Leukemia 2001; 15: 1232–1239.

    Article  CAS  PubMed  Google Scholar 

  25. Dalton WS, Cress AE, Alberts DS, Trent JM . Cytogenetic and phenotypic analysis of a human colon carcinoma cell line resistant to mitoxantrone. Cancer Res 1988; 48: 1882–1888.

    CAS  PubMed  Google Scholar 

  26. Durie BGM, Dalton WS . Reversal of drug-resistance in multiple myeloma with verapamil. Br J Haematol 1988; 68: 203–206.

    Article  CAS  PubMed  Google Scholar 

  27. Hazlehurst LA, Foley NE, Gleason-Guzman MC, Hacker MP, Cress AE, Greenberger LW et al. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res 1999; 59: 1021–1028.

    CAS  PubMed  Google Scholar 

  28. Sezer O, Jakob C, Eucker J, Niemoller K, Gatz F, Wernecke K et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 2001; 66: 83–88.

    Article  CAS  PubMed  Google Scholar 

  29. Podar K, Tai YT, Lin BK, Narsimhan RP, Sattler M, Kijima T et al. Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation. J Biol Chem 2002; 277: 7875–7881.

    Article  CAS  PubMed  Google Scholar 

  30. Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC . Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 1993; 82: 3712–3720.

    CAS  PubMed  Google Scholar 

  31. Faid L, Van RI, De Waele M, Facon T, Schots R et al. Adhesive interactions between tumour cells and bone marrow stromal elements in human multiple myeloma. Eur J Haematol 1996; 57: 349–358.

    Article  CAS  PubMed  Google Scholar 

  32. Teicher BA, Herman TS, Holden SA, Wang YY, Pfeffer MR, Crawford JW et al. Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo. Science 1990; 247: 1457–1461.

    Article  CAS  PubMed  Google Scholar 

  33. Green SK, Frankel A, Kerbel RS . Adhesion-dependent multi-cellular drug resistance. Anticancer Drug Des 1999; 14: 153–168.

    CAS  PubMed  Google Scholar 

  34. Hazlehurst LA, Valkov N, Wisner L, Storey JA, Boulware D, Sullivan DM et al. Reduction in drug-induced DNA double-strand breaks associated with beta1 integrin-mediated adhesion correlates with drug resistance in U937 cells. Blood 2001; 98: 1897–1903.

    Article  CAS  PubMed  Google Scholar 

  35. Sanz-Rodriguez F, Ruiz-Velasco N, Pascual-Salcedo D, Teixido J . Characterization of VLA-4-dependent myeloma cell adhesion to fibronectin and VCAM-1. Br J Haematol 1999; 107: 825–834.

    Article  CAS  PubMed  Google Scholar 

  36. Bellamy WT, Richter L, Frutiger Y, Grogan TM . Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res 1999; 59: 728–733.

    CAS  PubMed  Google Scholar 

  37. Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T et al. Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration. Blood 2001; 98: 428–435.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NCI Grants CA77859, CA82533, CA76296 (H Lee Moffitt Cancer Center Core Grant), the Multiple Myeloma Research Foundation, and the Peninsula Community Foundation for Myeloma Research. YN is supported by a fellowship from the Multiple Myeloma Research Foundation.

Author information

Authors and Affiliations

  1. Clinical Investigations, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Y Nefedova, T H Landowski & W S Dalton

  2. Department of Interdisciplinary Oncology, University of South Florida College of Medicine, Tampa, FL, USA

    Y Nefedova, T H Landowski & W S Dalton

Authors
  1. Y Nefedova
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T H Landowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W S Dalton
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nefedova, Y., Landowski, T. & Dalton, W. Bone marrow stromal-derived soluble factors and direct cell contact contribute to de novo drug resistance of myeloma cells by distinct mechanisms. Leukemia 17, 1175–1182 (2003). https://doi.org/10.1038/sj.leu.2402924

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402924

Keywords

This article is cited by

Search

Advanced search

Quick links