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B-cell-derived lymphotoxin promotes castration-resistant prostate cancer

Nature volume 464, pages 302–305 (2010)Cite this article

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An Erratum to this article was published on 17 June 2010

Abstract

Prostate cancer (CaP) progresses from prostatic intraepithelial neoplasia through locally invasive adenocarcinoma to castration-resistant metastatic carcinoma1. Although radical prostatectomy, radiation and androgen ablation are effective therapies for androgen-dependent CaP, metastatic castration-resistant CaP is a major complication with high mortality2. Androgens stimulate growth and survival of prostate epithelium and early CaP. Although most patients initially respond to androgen ablation, many develop castration-resistant CaP within 12–18 months2. Despite extensive studies, the mechanisms underlying the emergence of castration-resistant CaP remain poorly understood and their elucidation is critical for developing improved therapies. Curiously, castration-resistant CaP remains androgen-receptor dependent, and potent androgen-receptor antagonists induce tumour regression in castrated mice3. The role of inflammation in castration-resistant CaP has not been addressed, although it was reported that intrinsic NF-κB activation supports its growth4. Inflammation is a localized protective reaction to injury or infection, but it also has a pathogenic role in many diseases, including cancer5. Whereas acute inflammation is critical for host defence, chronic inflammation contributes to tumorigenesis and metastatic progression. The inflammation-responsive IκB kinase (IKK)-β and its target NF-κB have important tumour-promoting functions within malignant cells and inflammatory cells6. The latter, including macrophages and lymphocytes, are important elements of the tumour microenvironment7,8,9, but the mechanisms underlying their recruitment remain obscure, although they are thought to depend on chemokine and cytokine production10. We found that CaP progression is associated with inflammatory infiltration and activation of IKK-α, which stimulates metastasis by an NF-κB-independent, cell autonomous mechanism11. Here we show that androgen ablation causes infiltration of regressing androgen-dependent tumours with leukocytes, including B cells, in which IKK-β activation results in production of cytokines that activate IKK-α and STAT3 in CaP cells to enhance hormone-free survival.

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Figure 1: Androgen ablation induces tumour inflammatory infiltration.
Figure 2: Role of B cells and IKK-β in STAT3 activation and castration-resistant CaP emergence.
Figure 3: Role of IKK-α in emergence of castration-resistant CaP.
Figure 4: IKK-β-dependent lymphotoxin production by tumour-infiltrating B cells stimulates IKK-α-dependent androgen-free survival.

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References

  1. Isaacs, J. T. The biology of hormone refractory prostate cancer. Why does it develop? Urol. Clin. North Am. 26, 263–273 (1999)

    Article  CAS  Google Scholar 

  2. Gulley, J., Figg, W. D. & Dahut, W. L. Treatment options for androgen-independent prostate cancer. Clin. Adv. Hematol. Oncol. 1, 49–57 (2003)

    PubMed  Google Scholar 

  3. Tran, C. et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324, 787–790 (2009)

    Article  CAS  Google Scholar 

  4. Jin, R. J. et al. The nuclear factor-κB pathway controls the progression of prostate cancer to androgen-independent growth. Cancer Res. 68, 6762–6769 (2008)

    Article  CAS  Google Scholar 

  5. Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823–835 (2006)

    Article  CAS  Google Scholar 

  6. Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006)

    Article  CAS  Google Scholar 

  7. Balkwill, F., Charles, K. A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005)

    Article  CAS  Google Scholar 

  8. Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002)

    Article  CAS  Google Scholar 

  9. de Visser, K. E., Korets, L. V. & Coussens, L. M. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell 7, 411–423 (2005)

    Article  CAS  Google Scholar 

  10. Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008)

    Article  CAS  Google Scholar 

  11. Luo, J. L. et al. Nuclear cytokine activated IKKα controls prostate cancer metastasis by repressing maspin. Nature 446, 690–694 (2007)

    Article  CAS  Google Scholar 

  12. Bai, A., Higham, E., Eisen, H. N., Wittrup, K. D. & Chen, J. Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice. Proc. Natl Acad. Sci. USA 105, 13003–13008 (2008)

    Article  CAS  Google Scholar 

  13. Ellwood-Yen, K. et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 4, 223–238 (2003)

    Article  CAS  Google Scholar 

  14. Park, B. K. et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nature Med. 13, 62–69 (2007)

    Article  CAS  Google Scholar 

  15. Wen, D. et al. A selective small molecule IκB kinase β inhibitor blocks nuclear factor κB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes, and mast cells. J. Pharmacol. Exp. Ther. 317, 989–1001 (2006)

    Article  CAS  Google Scholar 

  16. Legler, D. F. et al. B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J. Exp. Med. 187, 655–660 (1998)

    Article  CAS  Google Scholar 

  17. Chen, T., Wang, L. H. & Farrar, W. L. Interleukin 6 activates androgen receptor-mediated gene expression through a signal transducer and activator of transcription 3-dependent pathway in LNCaP prostate cancer cells. Cancer Res. 60, 2132–2135 (2000)

    CAS  PubMed  Google Scholar 

  18. Eriksen, K. W. et al. Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells. Leukemia 15, 787–793 (2001)

    Article  CAS  Google Scholar 

  19. Hamel, K. et al. Suppression of proteoglycan-induced arthritis by anti-CD20 B cell depletion therapy is mediated by reduction in autoantibodies and CD4+ T cell reactivity. J. Immunol. 180, 4994–5003 (2008)

    Article  CAS  Google Scholar 

  20. Worm, M. M., Tsytsykova, A. & Geha, R. S. CD40 ligation and IL-4 use different mechanisms of transcriptional activation of the human lymphotoxin α promoter in B cells. Eur. J. Immunol. 28, 901–906 (1998)

    Article  CAS  Google Scholar 

  21. Tumanov, A. V. et al. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol. Rev. 195, 106–116 (2003)

    Article  CAS  Google Scholar 

  22. Lee, Y. et al. Recruitment and activation of naive T cells in the islets by lymphotoxin β receptor-dependent tertiary lymphoid structure. Immunity 25, 499–509 (2006)

    Article  CAS  Google Scholar 

  23. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β-dependent adaptive immunity against tumors. Nature Med. 15, 1170–1178 (2009)

    Article  CAS  Google Scholar 

  24. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002)

    Article  CAS  Google Scholar 

  25. Sakurai, T. et al. Hepatocyte necrosis induced by oxidative stress and IL-1 α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14, 156–165 (2008)

    Article  CAS  Google Scholar 

  26. Nimmerjahn, F. & Ravetch, J. V. Fc-receptors as regulators of immunity. Adv. Immunol. 96, 179–204 (2007)

    Article  CAS  Google Scholar 

  27. Bonizzi, G. et al. Activation of IKKα target genes depends on recognition of specific κB binding sites by RelB:p52 dimers. EMBO J. 23, 4202–4210 (2004)

    Article  CAS  Google Scholar 

  28. Kortylewski, M. & Yu, H. Stat3 as a potential target for cancer immunotherapy. J. Immunother. 30, 131–139 (2007)

    Article  CAS  Google Scholar 

  29. Smith, P. C., Hobisch, A., Lin, D. L., Culig, Z. & Keller, E. T. Interleukin-6 and prostate cancer progression. Cytokine Growth Factor Rev. 12, 33–40 (2001)

    Article  CAS  Google Scholar 

  30. Liu, X., Plummer, S. J., Nock, N. L., Casey, G. & Witte, J. S. Nonsteroidal antiinflammatory drugs and decreased risk of advanced prostate cancer: modification by lymphotoxin alpha. Am. J. Epidemiol. 164, 984–989 (2006)

    Article  Google Scholar 

  31. Greenberg, N. M. et al. Prostate cancer in a transgenic mouse. Proc. Natl Acad. Sci. USA 92, 3439–3443 (1995)

    Article  CAS  Google Scholar 

  32. Wu, X. et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech. Dev. 101, 61–69 (2001)

    Article  CAS  Google Scholar 

  33. Kuhn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995)

    Article  CAS  Google Scholar 

  34. Kim, S. et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457, 102–106 (2009)

    Article  CAS  Google Scholar 

  35. Watson, P. A. et al. Context-dependent hormone-refractory progression revealed through characterization of a novel murine prostate cancer cell line. Cancer Res. 65, 11565–11571 (2005)

    Article  CAS  Google Scholar 

  36. Zheng, B. et al. CXCL13 neutralization reduces the severity of collagen-induced arthritis. Arthritis Rheum. 52, 620–626 (2005)

    Article  CAS  Google Scholar 

  37. Izmailova, E. S. et al. Use of molecular imaging to quantify response to IKK-2 inhibitor treatment in murine arthritis. Arthritis Rheum. 56, 117–128 (2007)

    Article  CAS  Google Scholar 

  38. Luo, J. L., Maeda, S., Hsu, L. C., Yagita, H. & Karin, M. Inhibition of NF-κB in cancer cells converts inflammation-induced tumor growth mediated by TNFα to TRAIL-mediated tumor regression. Cancer Cell 6, 297–305 (2004)

    Article  CAS  Google Scholar 

  39. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C. Sawyers for myc-CaP cells, L. Coussens for JH–/– (FVB) mice, Y. X. Fu for LTβR-Ig fusion protein, R. Rickert for help with B-cell phenotyping, H. Cheroutre for flow cytometer use and C. Ware for bone marrow. M.A. was supported by Fondazione Italiana per la Ricerca sul Cancro and American-Italian Cancer Foundation fellowships. J.-L.L. was supported by a Life Science Research Fellowship. Work in M.K.’s laboratory was supported by grants from the National Institutes of Health, the US Army Medical Research and Material Command and Prostate Cancer Foundation. M.K. is an American Cancer Society Research Professor.

Author Contributions M.A., J.-L.L. and M.K. designed the study; M.A., J.-L.L. and S.G. performed research; S.N. provided lymphotoxin-deficient mice; M.A. and M.K. analysed data and wrote the paper.

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Author notes

  1. Massimo Ammirante and Jun-Li Luo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology and Cancer Center, Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA,

    Massimo Ammirante, Sergei Grivennikov & Michael Karin

  2. Department of Cancer Biology, Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, Florida 33458, USA,

    Jun-Li Luo

  3. Laboratory of Molecular Immunology, Engelhardt Institute of Molecular Biology, 119991, Moscow, Russia ,

    Sergei Nedospasov

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  1. Massimo Ammirante
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Correspondence to Michael Karin.

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Ammirante, M., Luo, JL., Grivennikov, S. et al. B-cell-derived lymphotoxin promotes castration-resistant prostate cancer. Nature 464, 302–305 (2010). https://doi.org/10.1038/nature08782

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