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

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.

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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.

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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).

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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.

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Correspondence to Christine Dierks or Markus Warmuth.

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The authors declare no competing financial interests.

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

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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

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