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 Paper
  • Published:

The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications

Abstract

In this study we demonstrate that tumor necrosis factor α (TNFα) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-κB activation, in MM.1S multiple myeloma (MM) cells. TNFα also activates NF-κB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNFα in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2–4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNFα-induced NF-κB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNFα may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.

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

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Akira S, Hirano T, Taga T, Kishimoto T . 1990 FASEB Journal 4: 2860–2867

  • Borset M, Waage A, Brekke OL, Helseth E . 1994 Eur. J. Haematol. 53: 31–37

  • Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . 1999 Immunity 10: 105–115

  • Chauhan D, Kharbanda S, Ogata A, Urashima M, Teoh G, Robertson M, Kufe DW, Anderson KC . 1997 Blood 89: 227–234

  • Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC . 2000 J. Biol. Chem. 275: 27845–27850

  • Chauhan D, Uchiyama H, Akbarali Y, Urashima M, Yamamoto KI, Libermann TA, Anderson KC . 1996 Blood 87: 1104–1112

  • Corral LG, Haslett PAJ, Muller GW, Chen R, Wong L-M, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G . 1999 J. Immunol. 163: 380–386

  • D'Amato RJ, Loughman MS, Flynn E, Folkman J . 1994 Proc. Natl. Acad. Sci. USA 91: 4082–4085

  • Damiano JS, Cress AE, Hazlehurst LA, Shtil AA, Dalton WS . 1999 Blood 93: 1658–1667

  • Dankar B, Padro T, Leo R, Feldman B, Kropff M, Mesters RM, Serve H, Berdel WE, Kienast J . 2000 Blood 95: 2630–2336

  • Davies F, Rollinson S, Rawstron A, Roman E, Richards S, Drayson M, Child J, Morgan G . 2000 J. Clin. Oncol. 18: 2843–2851

  • Davies FE, Raje N, Hideshima T, Lentzsch S, Young G, Tai YT, Lin B, Podar K, Gupta D, Chauhan D, Treon SP, Richardson PG, Schlossman RL, Morgan G, Muller GW, Stirling DI, Anderson KC . 2001 Blood in press

  • Filella X, Blade J, Guillermo A, Molina R, Rozman C, Ballesta A . 1996 Canc. Detec. and Preven. 20: 52–56

  • Garrett R, Durie B, Nedwin G, Gillespie A, Bringman T, Sabatini M, Bertolini D, Mundy G . 1987 New Engl. J. Med. 317: 526–632

  • Gupta D, Treon SP, Shima Y, Hideshima T, Podar K, Tai YT, Lin B, Lentzsch S, Davies FE, Chauhan D, Schlossman RL, Richardson PG, Ralph P, Wu L, Payvandi F, Muller G, Stirling DI, Anderson KC . 2001 Leukemia in press

  • Haslett P, Corral L, Albert M, Kapla G . 1998 J. Exp. Med. 187: 1885–1892

  • Hideshima T, Chauhan D, Shima Y, Raje N, Davies FE, Tai Y-T, Treon S, Lin B, Schlossman RL, Richardson P, Muller G, Stirling DI, Anderson KC . 2000 Blood 96: 2943–2950

  • Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliot PJ, Adams J, Anderson KC . 2001 Cancer Res. 61: 3071–3076

  • Jourdan M, Tarte K, Legouffe E, Brochier J, Rossi J, Klein B . 1999 Eur. Cytokine Network 10: 65–70

  • Junn E, Lee K, Ju H, Han S, Im J, Kang H, Lee T, Bae Y, Ha K, Ha K, Lee Z, Rhee S, Choi I . 2000 J. Immunol. 165: 2190–2197

  • Kim I, Uchiyama H, Chauhan D, Anderson KC . 1994 Brit. J. Hematol. 87: 483–493

  • Li P, Sanz I, O'Keefe R, Schwarz E . 2000 J. Immunol. 164: 5990–5997

  • Lichtenstein A, Berenson J, Norman D, Chang M, Carlile A . 1989 Blood 74: 1266–1273

  • Lichtenstein A, Tu Y, Fady C, Vescio R, Berenson J . 1995 Cell. Immunol. 162: 248–255

  • Marriott J, Westby M, Cookson S, Guckian M, Goodbourn S, Muller G, Shire M, Stirling D, Dalgleish A . 1998 J. Immunol. 161: 4236–4243

  • Ogata A, Chauhan D, Teoh G, Treon SP, Urashima M, Schlossman RL, Anderson KC . 1997 J. Immunol. 159: 2212–2221

  • Palombella V, Conner E, Fuseler J, Destree A, Davis J, Laroux F, Wolf R, Huang J, Brand S, Elliot P, Lazarus D, McCormack T, Parent L, Stein R, Adams J, Grisham M . 1998 Proc. Natl. Acad. Sci. USA 95: 15671–15676

  • Podar K, Tai YT, Davies FE, Lentzsch S, Sattler M, Hideshima T, Lin BK, Gupta D, Shima Y, Chauhan D, Mitsiades C, Raje N, Anderson KC . 2001 Blood in press

  • Raje N, Anderson KC . 1999 N. Engl. J. Med. 341: 1606–1609

  • Ray A, Sassone-Corsi P, Sehgal P . 1989 Mol. Cell. Biol. 9: 5537–5547

  • Sati H, Greaves M, Apperley J, Russell G, Croucher P . 1999 Brit. J. Haematol. 104: 350–357

  • Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Siegel D, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeldis J, Barlogie B . 1999 N. Engl. J. Med. 341: 1565–1571

  • Teoh G, Anderson KC . 1997 Hematol/Oncol. Clin. N. Amer. 11: 27–42

  • Treon SP, Mitsiades C, Mitsiades N, Young G, Doss D, Schlossman R, Anderson KC . 2001 J. Immunotherapy in press

  • Uchiyama H, Barut BA, Chauhan D, Cannistra SA, Anderson KC . 1992 Blood 80: 2306–2314

  • Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC . 1993 Blood 82: 3712–3720

  • Urashima M, Ogata A, Chauhan D, Hatziyanni M, Vidriales MB, Dedera DA, Schlossman RL, Anderson KC . 1996 Blood 87: 1928–1938

  • Urashima M, Teoh G, Chauhan D, Hoshi Y, Ogata A, Treon SP, Schlossman RL, Anderson KC . 1997 Blood 90: 279–289

  • Vacca A, Ribatti D, Presta M, Minischetti M, Iurlaro M, Ria R, Albini A, Bussolino F, Dammacco F . 1999 Blood 93: 3064–3073

Download references

Acknowledgements

Supported by National Institutes of Health Grant PO-1 78378 and the Doris Duke Distinguished Clinical Research Scientist Award to KC Anderson.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenneth C Anderson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hideshima, T., Chauhan, D., Schlossman, R. et al. The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20, 4519–4527 (2001). https://doi.org/10.1038/sj.onc.1204623

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204623

Keywords

This article is cited by

Search

Quick links