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.

  • Article
  • Published:

Essential role of stromally induced hedgehog signaling in B-cell malignancies

Nature Medicine volume 13, pages 944–951 (2007)Cite this article

Abstract

Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Eμ-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.

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: Hedgehog ligands provided by stromal cells from lymphoid organs are survival factors for lymphoma and multiple myeloma cells.
Figure 2: Hh pathway inhibition induces apoptosis in stroma-dependent lymphoma cells.
Figure 3: Constitutive Hh pathway activation in Myc-lymphoma cells induces highly proliferative lymphomas in the skin.
Figure 4: Overexpression of hedgehog pathway members Fused and Gli1 or Bcl2, but not loss of the Cdkn2a-Arf locus, can inhibit cyclopamine-induced apoptosis in Myc-lymphomas.
Figure 5: Hedgehog pathway inhibition abrogates lymphoma expansion in vivo.

Similar content being viewed by others

References

  1. Kawano, M. et al. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332, 83–85 (1988).

    Article  CAS  Google Scholar 

  2. Tassone, P. et al. Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu in vivo model of human multiple myeloma. Clin. Cancer Res. 11, 4251–4258 (2005).

    Article  CAS  Google Scholar 

  3. Li, Y. et al. DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7. Cancer Biol. Ther. 2, 187–193 (2003).

    Article  Google Scholar 

  4. Kimlinger, T. et al. Differential expression of vascular endothelial growth factors and their receptors in multiple myeloma. Haematologica 91, 1033–1040 (2006).

    CAS  PubMed  Google Scholar 

  5. Moller, C., Stromberg, T., Juremalm, M., Nilsson, K. & Nilsson, G. Expression and function of chemokine receptors in human multiple myeloma. Leukemia 17, 203–210 (2003).

    Article  CAS  Google Scholar 

  6. Jundt, F. et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood 103, 3511–3515 (2004).

    Article  CAS  Google Scholar 

  7. Georgii-Hemming, P. et al. Insulin-like growth factor I is a growth and survival factor in human multiple myeloma cell lines. Blood 88, 2250–2258 (1996).

    CAS  PubMed  Google Scholar 

  8. Kobune, M. et al. Indian hedgehog gene transfer augments hematopoietic support of human stromal cells including NOD/SCID–β 2 m−/− repopulating cells. Blood 104, 1002–1009 (2004).

    Article  CAS  Google Scholar 

  9. Sacedon, R. et al. Sonic hedgehog is produced by follicular dendritic cells and protects germinal center B cells from apoptosis. J. Immunol. 174, 1456–1461 (2005).

    Article  CAS  Google Scholar 

  10. Stewart, G.A. et al. Sonic hedgehog signaling modulates activation of and cytokine production by human peripheral CD4+ T cells. J. Immunol. 169, 5451–5457 (2002).

    Article  CAS  Google Scholar 

  11. Dyer, M.A., Farrington, S.M., Mohn, D., Munday, J.R. & Baron, M.H. Indian hedgehog activates hematopoiesis and vasculogenesis and can respecify prospective neurectodermal cell fate in the mouse embryo. Development 128, 1717–1730 (2001).

    CAS  Google Scholar 

  12. Gering, M. & Patient, R. Hedgehog signaling is required for adult blood stem cell formation in zebrafish embryos. Dev. Cell 8, 389–400 (2005).

    Article  CAS  Google Scholar 

  13. Lee, J., Platt, K.A., Censullo, P. & Ruiz i Altaba, A. Gli1 is a target of Sonic hedgehog that induces ventral neural tube development. Development 124, 2537–2552 (1997).

    CAS  PubMed  Google Scholar 

  14. Marigo, V. & Tabin, C.J. Regulation of patched by sonic hedgehog in the developing neural tube. Proc. Natl. Acad. Sci. USA 93, 9346–9351 (1996).

    Article  CAS  Google Scholar 

  15. Duman-Scheel, M., Weng, L. & Xin, S. Hedgehog regulates cell growth and proliferation by inducing Cyclin D and Cyclin E. Nature 417, 299–344 (2002).

    Article  CAS  Google Scholar 

  16. Xie, J. et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998).

    Article  CAS  Google Scholar 

  17. Goodrich, L.V. & Scott, M.P. Hedgehog and Patched in neural development and disease. Neuron 21, 1243–1257 (1998).

    Article  CAS  Google Scholar 

  18. Marino, S. Medulloblastoma: developmental mechanisms out of control. Trends Mol. Med. 11, 17–22 (2005).

    Article  CAS  Google Scholar 

  19. Aszterbaum, M. et al. Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat. Med. 5, 1285–1291 (1999).

    Article  CAS  Google Scholar 

  20. Tostar, U. et al. Deregulation of the hedgehog signaling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J. Pathol. 208, 17–25 (2006).

    Article  CAS  Google Scholar 

  21. Oro, A.E. et al. Basal cell carcinomas in mice overexpressing sonic hedgehog. Science 276, 817–821 (1997).

    Article  CAS  Google Scholar 

  22. Watkins, D.N. et al. Hedgehog signaling within airway epithelial progenitors and in small-cell lung cancer. Nature 422, 313–317 (2003).

    Article  CAS  Google Scholar 

  23. Karhadkar, S.S. et al. Hedgehog signaling in prostate regeneration, neoplasia and metastasis. Nature 431, 707–712 (2004).

    Article  CAS  Google Scholar 

  24. Thayer, S.P., di Magliano, M.P. & Heiser, P.W. Hedgehog is an early and late mediator of pancreatic cancer tumourigenesis. Nature 425, 851–856 (2003).

    Article  CAS  Google Scholar 

  25. Berman, D.M., Karhadkar, S.S. & Maitra, A. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors. Nature 425, 846–851 (2003).

    Article  CAS  Google Scholar 

  26. Adams, J.M. et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318, 533–538 (1985).

    Article  CAS  Google Scholar 

  27. Serrano, M. et al. Role of the INK4a locus in tumor suppression and cell mortality. Cell 85, 27–37 (1996).

    Article  CAS  Google Scholar 

  28. Park, S.S. et al. Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice. Cancer Res. 65, 1306–1315 (2005).

    Article  CAS  Google Scholar 

  29. Wu, X. et al. Purmorphamine induces osteogenesis by activation of the Hedgehog signaling pathway. Chem. Biol. 11, 1229–1238 (2004).

    Article  CAS  Google Scholar 

  30. Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).

    Article  CAS  Google Scholar 

  31. Ericson, J., Morton, S., Kawakami, A., Roelink, H. & Jessell, T.M. Two critical periods of Sonic Hedgehog signaling required for the specification of motor neuron identity. Cell 87, 661–673 (1996).

    Article  CAS  Google Scholar 

  32. Chen, J.K., Taipale, J., Young, K.E., Maiti, T. & Beachy, P.A. Small molecule modulation of Smoothened activity. Proc. Natl. Acad. Sci. USA 99, 14071–14076 (2002).

    Article  CAS  Google Scholar 

  33. Cooper, M.K., Porter, J.A., Young, K.E. & Beachy, P.A. Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280, 1603–1607 (1998).

    Article  CAS  Google Scholar 

  34. Burger, M. et al. Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. Blood 106, 1824–1830 (2005).

    Article  CAS  Google Scholar 

  35. Lowrey, J.A. et al. Sonic hedgehog promotes cell cycle progression in activated peripheral CD4+ T lymphocytes. J. Immunol. 169, 1869–1875 (2002).

    Article  CAS  Google Scholar 

  36. Dai, P. et al. Sonic Hedgehog-induced activation of the Gli1 promoter is mediated by GLI3. J. Biol. Chem. 274, 8143–8152 (1999).

    Article  CAS  Google Scholar 

  37. Regl, G., Kasper, M. & Schnidar, H. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 64, 7724–7731 (2004).

    Article  CAS  Google Scholar 

  38. van Lohuizen, M. et al. Identification of cooperating oncogenes in Eμ-myc transgenic mice by provirus tagging. Cell 65, 737–752 (1991).

    Article  CAS  Google Scholar 

  39. Guney, I., Wu, S. & Sedivy, J.M. Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16INK4a. Proc. Natl. Acad. Sci. USA 103, 3645–3650 (2006).

    Article  CAS  Google Scholar 

  40. Strasser, A. et al. Enforced BCL2 expression in B-lymphoid cells prolongs antibody responses and elicits autoimmune disease. Proc. Natl. Acad. Sci. USA 88, 8661–8665 (1991).

    Article  CAS  Google Scholar 

  41. Knudson, C.M. et al. Bax-deficient mice with lymphoid hyperplasia and male germ cell death. Science 270, 96–99 (1995).

    Article  CAS  Google Scholar 

  42. Woo, M. et al. Essential contribution of Caspase 3/CPP32 to apoptosis and its associated nuclear changes. Genes Dev. 12, 806–819 (1998).

    Article  CAS  Google Scholar 

  43. Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  CAS  Google Scholar 

  44. Dalla-Favera, R. et al. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc. Natl. Acad. Sci. USA 79, 7824–7827 (1982).

    Article  CAS  Google Scholar 

  45. Muller, J.R., Janz, S. & Potter, M. Differences between Burkitt's lymphomas and mouse plasmacytomas in the immunoglobulin heavy chain/c-myc recombinations that occur in their chromosomal translocations. Cancer Res. 55, 5012–5018 (1995).

    CAS  PubMed  Google Scholar 

  46. Dang, C.V., O'Donnell, K.A. & Juopperi, T. The great MYC escape in tumorigenesis. Cancer Cell 8, 177–178 (2005).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank P. Gordon for formulating cyclopamine. We thank N. Gray for critically reading the manuscript and helpful advice. We thank J. Watson for immunohistochemistry support, J. Goldstein for support with clonality analysis of lymphomas and C. Trussel for help with flow cytometry. Casp3−/− mice were kindly provided by K. A. Roth (Washington University School of Medicine).

Author information

Authors and Affiliations

  1. Department of Pharmacology and Department of Medicinal Chemistry, Kinase Biology/In-vivo Oncology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, 92121, California, USA

    Christine Dierks, Ronak Beigi, Nathan P Englund, Gui-Rong Guo, Peter Schultz & Markus Warmuth

  2. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92121, California, USA

    Christine Dierks, Jovana Grbic & Peter Schultz

  3. Department of Hematology/Oncology, University of Freiburg, Hugstetter Strasse 55, Freiburg, 79111, Germany

    Katja Zirlik, Hendrik Veelken, Monika Engelhardt & Roland Mertelsmann

  4. Novartis Institute for BioMedical Research, 250 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Joseph F Kelleher

Authors
  1. Christine Dierks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jovana Grbic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katja Zirlik
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ronak Beigi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nathan P Englund
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gui-Rong Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hendrik Veelken
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Monika Engelhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roland Mertelsmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joseph F Kelleher
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Schultz
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Markus Warmuth
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

C.D. designed and performed in vitro and in vivo experiments, generated figures, analyzed data and wrote the manuscript. J.G. helped generate lymphoma cell lines. K.Z., H.V., R.M. and M.E. organized human samples and paraffin sections and critically reviewed the manuscript. R.B. performed animal studies. N.P.E. performed TaqMan PCR and proliferation assays. G.-R.G. performed immunohistochemistry. J.F.K. provided cyclopamine and critically reviewed the manuscript. P.S. reviewed the manuscript and M.W. supervised the study, contributed crucial ideas to the project and reviewed the manuscript.

Corresponding authors

Correspondence to Christine Dierks or Markus Warmuth.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Table 1, Supplementary Methods (PDF 524 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dierks, C., Grbic, J., Zirlik, K. et al. Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 13, 944–951 (2007). https://doi.org/10.1038/nm1614

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1614

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing