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:

Normal Hemopoiesis and Stemcellology

The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A

Leukemia volume 15, pages 1102–1110 (2001)Cite this article

Abstract

The mesenchymal stroma has been shown to play a crucial role in the development of multiple myeloma, partly by secretion of interleukin (IL)-6, that serves as a growth factor for myeloma cells. However, it is still unclear which other stromal molecules are involved in the pathogenesis of this disease. We chose, as a model system, a mouse plasmacytoma cell line, which does not respond to IL-6. We found that the formation of mouse plasmacytoma tumors, in an in vivo skin transplantation model, is facilitated by co-injection of these tumor cells along with a mesenchymal stromal cell. The tumor promoting effect of the stroma was reproduced in an in vitromodel; stromal cells induced the proliferation of plasmacytoma cells under serum-free conditions. This growth promotion could not be mimicked by a series of cytokines including IL-6 and insulin-like growth factor (IGF)-I implying a role for yet unidentified stromal factors. The in vivo formation of plasmacytoma tumors was reduced following administration of activin A, a cytokine member of the transforming growth factor (TGF)β superfamily. Furthermore, the in vitro growth promoting effect of the stroma was abrogated by basic fibroblast growth factor (bFGF) which induced a higher stromal expression of activin A. Our results thus show that mesenchymal stroma expresses plasmacytoma growth stimulating activities that overcome the low constitutive level of the plasmacytoma inhibitor, activin A. The expression of activin A is upregulated by bFGF rendering the stroma suppressive for plasmacytoma growth. The balance between the expression of these regulators may contribute to mesenchymal stroma activity and influence the progression of multiple myeloma.

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
Figure 6

Similar content being viewed by others

References

  1. van den Hooff A . Stromal involvement in malignant growth Adv Cancer Res 1988 50: 159–196

    Article  CAS  PubMed  Google Scholar 

  2. Zipori D . Stromal cells in tumor growth and regression Cancer J 1990 3: 164–169

    Google Scholar 

  3. Tartour E, Fridman WH . Cytokines and cancer Int Rev Immunol 1998 16: 683–704

    Article  CAS  PubMed  Google Scholar 

  4. Zipori D . Conditions required for the inhibition of in vitro growth of a mouse myeloma cell line by adherent bone marrow cells Cell Tissue Kinet 1981 14: 479–489

    CAS  PubMed  Google Scholar 

  5. Peled A, Lee BC, Sternberg D, Toledo J, Aracil M, Zipori D . Interactions between leukemia cells and bone marrow stromal cells: stroma-supported growth vs. serum dependence and the roles of TGF-beta and M-CSF Exp Hematol 1996 24: 728–737

    CAS  PubMed  Google Scholar 

  6. Van Riet I . Homing mechanisms of myeloma cells Pathol Biol 1999 47: 98–108

    CAS  PubMed  Google Scholar 

  7. Grigorieva I, Thomas X, Epstein J . The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone Exp Hematol 1998 26: 597–603

    CAS  PubMed  Google Scholar 

  8. Faid L, Van Riet I, De Waele M, Facon T, Schots R, Lacor P, Van Camp B . 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 

  9. Van Riet I, De Greef C, Aharchi F, Woischwill C, De Waele M, Bakkus M, Lacor P, Schots R, Van Camp B . Establishment and characterization of a human stroma-dependent myeloma cell line (MM5.1) and its stroma-independent variant (MM5.2) Leukemia 1997 11: 284–293

    Article  CAS  PubMed  Google Scholar 

  10. Van Riet I, Vanderkerken K, de Greef C, Van Camp B . Homing behaviour of the malignant cell clone in multiple myeloma Med Oncol 1998 15: 154–164

    Article  CAS  PubMed  Google Scholar 

  11. Hallek M, Bergsagel PL, Anderson KC . Multiple myeloma: increasing evidence for a multistep transformation process Blood 1998 91: 3–21

    CAS  PubMed  Google Scholar 

  12. Georgii-Hemming P, Stromberg T, Janson ET, Stridsberg M, Wiklund HJ, Nilsson K . The somatostatin analog octreotide inhibits growth of interleukin-6 (IL-6)-dependent and IL-6-independent human multiple myeloma cell lines Blood 1999 93: 1724–1731

    CAS  PubMed  Google Scholar 

  13. Klein B, Zhang XG, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R . Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6 Blood 1989 73: 517–526

    CAS  PubMed  Google Scholar 

  14. Kawano M, Kuramoto A, Hirano T, Kishimoto T . Cytokines as autocrine growth factors in malignancies Cancer Surv 1989 8: 905–919

    CAS  PubMed  Google Scholar 

  15. Schwab G, Siegall CB, Aarden LA, Neckers LM, Nordan RP . Characterization of an interleukin-6-mediated autocrine growth loop in the human multiple myeloma cell line, U266 Blood 1991 77: 587–593

    CAS  PubMed  Google Scholar 

  16. Frassanito MA, Silvestris S, Silvestris N, Cafforio P, Camarda G, Iodice G, Dammacco F . Fas/Fas ligand (FasL)-deregulated apoptosis and IL-6 insensitivity in highly malignant myeloma cells Clin Exp Immunol 1998 114: 179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zipori D, Krupsky M, Resnitzky P . Stromal cell effects on clonal growth of tumors Cancer 1987 60: 1757–1762

    Article  CAS  PubMed  Google Scholar 

  18. Zipori D, Toledo J, von der Mark K . Phenotypic heterogeneity among stromal cell lines from mouse bone marrow disclosed in their extracellular matrix composition and interactions with normal and leukemic cells Blood 1985 66: 447–455

    CAS  PubMed  Google Scholar 

  19. Zipori D, Tamir M, Toledo J, Oren T . Differentiation stage and lineage-specific inhibitor from the stroma of mouse bone marrow that restricts lymphoma cell growth Proc Natl Acad Sci USA 1986 83: 4547–4551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Brosh N, Sternberg D, Honigwachs-Sha'anani J, Lee BC, Shav-Tal Y, Tzehoval E, Shulman LM, Toledo J, Hacham Y, Carmi P, Jiang W, Sasse J, Horn F, Burshtein Y, Zipori D . The plasmacytoma growth inhibitor restrictin-P is an antagonist of interleukin 6 and interleukin 11. Identification as a stroma-derived activin A J Biol Chem 1995 270: 29594–29600

    Article  CAS  PubMed  Google Scholar 

  21. Sternberg D, Honigwachs-sha'anani J, Brosh N, Malik Z, Burstein Y, Zipori D . Restrictin-P/stromal activin A, kills its target cells via an apoptotic mechanism Growth Factors 1995 12: 277–287

    Article  CAS  PubMed  Google Scholar 

  22. Nishihara T, Okahashi N, Ueda N . Activin A induces apoptotic cell death Biochem Biophys Res Commun 1993 197: 985–991

    Article  CAS  PubMed  Google Scholar 

  23. Yu EW, Dolter KE, Shao LE, Yu J . Suppression of IL-6 biological activities by activin A and implications for inflammatory arthropathies Clin Exp Immunol 1998 112: 126–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Haynesworth SE, Baber MA, Caplan AI . Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha J Cell Physiol 1996 166: 585–592

    Article  CAS  PubMed  Google Scholar 

  25. Dolter KE, Palyash JC, Shao LE, Yu J . Analysis of activin A gene expression in human bone marrow stromal cells J Cell Biochem 1998 70: 8–21

    Article  CAS  PubMed  Google Scholar 

  26. Shao L, Frigon NL Jr, Sehy DW, Yu AL, Lofgren J, Schwall R, Yu J . Regulation of production of activin A in human marrow stromal cells and monocytes Exp Hematol 1992 20: 1235–1242

    CAS  PubMed  Google Scholar 

  27. Zipori D, Friedman A, Tamir M, Silverberg D, Malik Z . Cultured mouse marrow cell lines: interactions between fibroblastoid cells and monocytes J Cell Physiol 1984 118: 143–152

    Article  CAS  PubMed  Google Scholar 

  28. Zipori D, Duksin D, Tamir M, Argaman A, Toledo J, Z . M. Cultured mouse marrow stromal cell lines. II. Distinct subtypes differing in morphology, collagen types, myelopoietic factors, and leukemic cell growth modulating activities J Cell Physiol 1985 122: 81–90

    Article  CAS  PubMed  Google Scholar 

  29. Zipori D, Lee F . Introduction of interleukin-3 gene into stromal cells from the bone marrow alters hemopoietic differentiation but does not modify stem cell renewal Blood 1988 71: 586–596

    CAS  PubMed  Google Scholar 

  30. Zipori D . Cultured stromal cell lines from hemopoietic tissues. In: Tavassoli M (ed.) Handbook of the Hemopoietic Microenvironment Humana Press: Clifton, NJ 1989 pp 287–333

    Chapter  Google Scholar 

  31. Wilson R, Spier RE . Biochemistry of hybridoma technology Dev Biol Stand 1987 66: 161–167

    CAS  PubMed  Google Scholar 

  32. Breton J, La Fiura A, Bertolero F, Orsini G, Valsasina B, Ziliotto R, De Filippis V, Polverino de Laureto P, Fontana A . Structure, stability and biological properties of a N-terminally truncated form of recombinant human interleukin-6 containing a single disulfide bond Eur J Biochem 1995 227: 573–581

    Article  CAS  PubMed  Google Scholar 

  33. Mathews LS, Vale WW . Expression cloning of an activin receptor, a predicted transmembrane serine kinase Cell 1991 65: 973–982

    Article  CAS  PubMed  Google Scholar 

  34. Hashimoto M, Shoda A, Inoue S, Yamada R, Kondo T, Sakurai T, Ueno N, Muramatsu M . Functional regulation of osteoblastic cells by the interaction of activin-A with follistatin J Biol Chem 1992 267: 4999–5004

    CAS  PubMed  Google Scholar 

  35. Zipori D . In vitro proliferation of mouse lymphoblastoid cell lines: growth modulation by various populations of adherent cells Cell Tissue Kinet 1980 13: 287–298

    CAS  PubMed  Google Scholar 

  36. Uchimaru K, Motokura T, Takahashi S, Sakurai T, Asano S, Yamashita T . Bone marrow stromal cells produce and respond to activin A: interactions with basic fibroblast growth factor and platelet-derived growth factor Exp Hematol 1995 23: 613–618

    CAS  PubMed  Google Scholar 

  37. Sternberg D, Peled A, Shezen E, Abramsky O, Jiang W, Bertolero F, Zipori D . Control of stroma-dependent hemopoiesis by basic fibroblast growth factor: stromal phenotypic plasticity and modified myelopoietic functions Cyto Mol Ther 1996 2: 29–38

    CAS  Google Scholar 

  38. Otsuka T, Ogo T, Nakano T, Niiro H, Kuga S, Satoh H, Furukawa Y, Zipori D, Niho Y . Expression of the c-kit ligand and interleukin 6 genes in mouse bone marrow stromal cell lines Stem Cells 1994 12: 409–415

    Article  CAS  PubMed  Google Scholar 

  39. de Kretser DM, Hedger MP, Phillips DJ . Activin A and follistatin: their role in the acute phase reaction and inflammation J Endocrinol 1999 161: 195–198

    Article  CAS  PubMed  Google Scholar 

  40. Bergers G, Javaherian K, Lo KM, Folkman J, Hanahan D . Effects of angiogenesis inhibitors on multistage carcinogenesis in mice Science 1999 284: 808–812

    Article  CAS  PubMed  Google Scholar 

  41. Urashima M, Ogata A, Chauhan D, Hatziyanni M, Vidriales MB, Dedera DA, Schlossman RL, Anderson KC . Transforming growth factor-beta1: differential effects on multiple myeloma versus normal B cells Blood 1996 87: 1928–1938

    CAS  PubMed  Google Scholar 

  42. Robledo MM, Sanz-Rodriguez F, Hidalgo A, Teixido J . Differential use of very late antigen-4 and -5 integrins by hematopoietic precursors and myeloma cells to adhere to transforming growth factor-beta1-treated bone marrow stroma J Biol Chem 1998 273: 12056–12060

    Article  CAS  PubMed  Google Scholar 

  43. Thomas X, Anglaret B, Magaud JP, Epstein J, Archimbaud E . Interdependence between cytokines and cell adhesion molecules to induce interleukin-6 production by stromal cells in myeloma Leuk Lymphoma 1998 32: 107–119

    Article  CAS  PubMed  Google Scholar 

  44. 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 

  45. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T . Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas Nature 1988 332: 83–85

    Article  CAS  PubMed  Google Scholar 

  46. Spets H, Georgii-Hemming P, Siljason J, Nilsson K Jernberg-Wiklund H . Fas/APO-1 (CD95)-mediated apoptosis is activated by interferon-gamma and interferon-α in interleukin-6 (IL-6)-dependent and IL-6-independent multiple myeloma cell lines Blood 1998 92: 2914–2923

    CAS  PubMed  Google Scholar 

  47. Horton HM, Hernandez P, Parker SE, Barnhart KM . Antitumor effects of interferon-omega: in vivo therapy of human tumor xenografts in nude mice Cancer Res 1999 59: 4064–4068

    CAS  PubMed  Google Scholar 

  48. Arbiser JL, Karalis K, Viswanathan A, Koike C, Anand-Apte B, Flynn E, Zetter B, Majzoub JA . Corticotropin-releasing hormone stimulates angiogenesis and epithelial tumor growth in the skin J Invest Dermatol 1999 113: 838–842

    Article  CAS  PubMed  Google Scholar 

  49. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T . Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4 Science 1999 283: 845–848

    Article  CAS  PubMed  Google Scholar 

  50. Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S, Grabovsky V, Slav MM, Nagler A, Lider O, Alon R, Zipori D, Lapidot T . The chemokine SDF-1 activates the integrins LFA-1, VLA-4 and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice Blood 2000 95: 3289–3296

    CAS  PubMed  Google Scholar 

  51. Piacibello W, Sanavio F, Severino A, Dane A, Gammaitoni L, Fagioli F, Perissinotto E, Cavalloni G, Kollet O, Lapidot T, Aglietta M . Engraftment in nonobese diabetic severe combined immunodeficient mice of human CD34(+) cord blood cells after ex vivo expansion: evidence for the amplification and self-renewal of repopulating stem cells Blood 1999 93: 3736–3749

    CAS  PubMed  Google Scholar 

  52. Sporn MB, Roberts AB . Transforming growth factor-beta: recent progress and new challenges J Cell Biol 1992 119: 1017–1021

    Article  CAS  PubMed  Google Scholar 

  53. Huber TL, Zhou Y, Mead PE, Zon LI . Cooperative effects of growth factors involved in the induction of hematopoietic mesoderm Blood 1998 92: 4128–4137

    CAS  PubMed  Google Scholar 

  54. Murata M, Eto Y, Shibai H, Sakai M, Muramatsu M . Erythroid differentiation factor is encoded by the same mRNA as that of the inhibin beta A chain Proc Natl Acad Sci USA 1988 85: 2434–2438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Eramaa M, Hurme M, Stenman UH, Ritvos O . Activin A/erythroid differentiation factor is induced during human monocyte activation J Exp Med 1992 176: 1449–1452

    Article  CAS  PubMed  Google Scholar 

  56. Okafuji K, Kaku K, Seguchi M, Tanaka H, Azuno Y, Kaneko T . Effects of activin A/erythroid differentiation factor on erythroid and megakaryocytic differentiations of mouse erythroleukemia (Friend) cells: evidence for two distinct modes of cell response Exp Hematol 1995 23: 210–216

    CAS  PubMed  Google Scholar 

  57. Fidler IJ, Kumar R, Bielenberg DR, Ellis LM . Molecular determinants of angiogenesis in cancer metastasis Cancer J Sci Am 1998 4 (Suppl. 1): S58–66

    Google Scholar 

  58. Dooley DC, Oppenlander BK, Spurgin P, Mead JH, Novak FP, Plunkett M, Beckstead J, Heinrich MC . Basic fibroblast growth factor and epidermal growth factor downmodulate the growth of hematopoietic cells in long-term stromal cultures J Cell Physiol 1995 165: 386–397

    Article  CAS  PubMed  Google Scholar 

  59. Feng S, Wang F, Matsubara A, Kan M, McKeehan WL . Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells Cancer Res 1997 57: 5369–5378

    CAS  PubMed  Google Scholar 

  60. Guddo F, Fontanini G, Reina C, Vignola AM, Angeletti A, Bonsignore G . The expression of basic fibroblast growth factor (bFGF) in tumor-associated stromal cells and vessels is inversely correlated with non-small cell lung cancer progression Hum Pathol 1999 30: 788–794

    Article  CAS  PubMed  Google Scholar 

  61. Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, Albini A, Bussolino F, Dammacco F . 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 

  62. Plowright EE, Li Z, Bergsagel PL, Chesi M, Barber DL, Branch DR, Hawley RG, Stewart AK . Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis Blood 2000 95: 992–998

    CAS  PubMed  Google Scholar 

  63. San Miguel JF, Blade Creixenti J, Garcia-Sanz R . Treatment of multiple myeloma Haematologica 1999 84: 36–58

    CAS  PubMed  Google Scholar 

  64. Lenhoff S, Hjorth M, Holmberg E, Turesson I, Westin J, Nielsen JL, Wisloff F, Brinch L, Carlson K, Carlsson M, Dahl IM, Gimsing P, Hippe E, Johnsen H, Lamvik J, Lofvenberg E, Nesthus I, Rodjer S . Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: a population-based study. Nordic Myeloma Study Group Blood 2000 95: 7–11

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Israeli Ministry of Health Chief Scientist's Office, Jerusalem, by the Israel Cancer Association and a by the Israel Cancer Association through the ICA friends in Holland. We are indebted to Dr AF Parlow and the NIDDK's National Hormone & Pituitary Program for providing activin A and follistatin. Dov Zipori is an incumbent of the Joe and Celia Weinstein professorial chair at the Weizmann Institute of Science.

Author information

Authors and Affiliations

  1. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    T Shoham, D Sternberg, N Brosh, M Krupsky, M Barda-Saad & D Zipori

Authors
  1. T Shoham
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Sternberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Brosh
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Krupsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Barda-Saad
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Zipori
    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

Shoham, T., Sternberg, D., Brosh, N. et al. The promotion of plasmacytoma tumor growth by mesenchymal stroma is antagonized by basic fibroblast growth factor induced activin A. Leukemia 15, 1102–1110 (2001). https://doi.org/10.1038/sj.leu.2402145

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402145

Keywords

This article is cited by

Search

Advanced search

Quick links