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Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity

Nature Medicine volume 16, pages 483–489 (2010)Cite this article

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An Author Correction to this article was published on 14 February 2024

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Abstract

Conventional anticancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter antitumor drug activity. To address this limitation, we developed the tumor cell–specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (for example, myeloma, leukemia and solid tumors) stably expressing luciferase are cultured with nonmalignant accessory cells (for example, stromal cells) for selective quantification of tumor cell viability, in presence versus absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib resistance in leukemic cells. A stroma-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-κB, HIF-1α, myc, hTERT and IRF4; for biological aggressiveness; and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, shows more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anticancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stroma interactions.

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Figure 1: Stromal cells modify the response of diverse tumor cell types to various agents.
Figure 2: Effect of blocking IL-6 and IL-6 receptor on MM cell co-cultures with BMSCs.
Figure 3: Mechanisms of drug sensitivity modulation in the context of tumor-stroma interactions.
Figure 4: Enhanced activity of reversine in the presence of stromal cells.

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References

  1. Mueller, M.M. & Fusenig, N.E. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Karnoub, A.E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  3. Mitsiades, C.S., Mitsiades, N., Munshi, N.C. & Anderson, K.C. Focus on multiple myeloma. Cancer Cell 6, 439–444 (2004).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Hurt, E.M. et al. Overexpression of c-maf is a frequent oncogenic event in multiple myeloma that promotes proliferation and pathological interactions with bone marrow stroma. Cancer Cell 5, 191–199 (2004).

    Article  CAS  PubMed  Google Scholar 

  6. Hideshima, T. et al. Thalidomide and its analogs overcome drug resistance of human multiple myeloma cells to conventional therapy. Blood 96, 2943–2950 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Hideshima, T. et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res. 61, 3071–3076 (2001).

    CAS  PubMed  Google Scholar 

  8. Richardson, P.G. et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood 100, 3063–3067 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Richardson, P.G. et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N. Engl. J. Med. 348, 2609–2617 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Richardson, P.G. et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood 108, 3458–3464 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Richardson, P.G. et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 352, 2487–2498 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Mitsiades, C.S. et al. Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumors. Cancer Cell 5, 221–230 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Nefedova, Y., Cheng, P., Alsina, M., Dalton, W.S. & Gabrilovich, D.I. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 103, 3503–3510 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Shou, Y. et al. Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma. Proc. Natl. Acad. Sci. USA 97, 228–233 (2000).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mitsiades, C.S. et al. Activation of NF-kappaB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications. Oncogene 21, 5673–5683 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Shaffer, A.L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. Mitsiades, C.S. et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl. Acad. Sci. USA 101, 540–545 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Mitsiades, N. et al. Molecular sequelae of histone deacetylase inhibition in human malignant B cells. Blood 101, 4055–4062 (2003).

    Article  CAS  PubMed  Google Scholar 

  20. Keen, N. & Taylor, S. Aurora-kinase inhibitors as anticancer agents. Nat. Rev. Cancer 4, 927–936 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Mitsiades, N. et al. Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc. Natl. Acad. Sci. USA 99, 14374–14379 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  22. Opferman, J.T. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003).

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Yagoda, N. et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 447, 864–868 (2007).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  24. Smith, D.R. et al. Inhibition of interleukin 8 attenuates angiogenesis in bronchogenic carcinoma. J. Exp. Med. 179, 1409–1415 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Lust, J.A. & Donovan, K.A. The role of interleukin-1 beta in the pathogenesis of multiple myeloma. Hematol. Oncol. Clin. North Am. 13, 1117–1125 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Roodman, G.D. Role of the bone marrow microenvironment in multiple myeloma. J. Bone Miner. Res. 17, 1921–1925 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Zeller, K.I., Jegga, A.G., Aronow, B.J., O′Donnell, K.A. & Dang, C.V. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol. 4, R69 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yu, D., Cozma, D., Park, A. & Thomas-Tikhonenko, A. Functional validation of genes implicated in lymphomagenesis: an in vivo selection assay using a Myc-induced B-cell tumor. Ann. NY Acad. Sci. 1059, 145–159 (2005).

    Article  ADS  CAS  PubMed  Google Scholar 

  29. Lindvall, C. et al. Molecular characterization of human telomerase reverse transcriptase-immortalized human fibroblasts by gene expression profiling: activation of the epiregulin gene. Cancer Res. 63, 1743–1747 (2003).

    CAS  PubMed  Google Scholar 

  30. Ingram, W.J., Wicking, C.A., Grimmond, S.M., Forrest, A.R. & Wainwright, B.J. Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells. Oncogene 21, 8196–8205 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Nguyen, B.C. et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 20, 1028–1042 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Bhattacharya, B. et al. Gene expression in human embryonic stem cell lines: unique molecular signature. Blood 103, 2956–2964 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Kannan, K. et al. DNA microarrays identification of primary and secondary target genes regulated by p53. Oncogene 20, 2225–2234 (2001).

    Article  CAS  PubMed  Google Scholar 

  34. Shaughnessy, J.D. Jr. et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109, 2276–2284 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Dimopoulos, M. et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N. Engl. J. Med. 357, 2123–2132 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Weber, D.M. et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N. Engl. J. Med. 357, 2133–2142 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. San Miguel, J.F. et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N. Engl. J. Med. 359, 906–917 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. Mitsiades, C.S. et al. Fluorescence imaging of multiple myeloma cells in a clinically relevant SCID/NOD in vivo model: biologic and clinical implications. Cancer Res. 63, 6689–6696 (2003).

    CAS  PubMed  Google Scholar 

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Acknowledgements

Supported by the Dunkin Donuts Rising Stars program at the Dana-Farber Cancer Institute (C.S.M.), the Chambers Medical Foundation (C.S.M. and P.G.R.), the Steven Cobb Foundation (D.W.M., C.S.M.) and US National Institutes of Health grant R01CA050947 (C.S.M. and K.C.A.). We wish to thank T. Libermann and M. Joseph-Bruno (Harvard Institutes of Medicine Genomics Core) for generation of gene expression data and L. Buon for help with bioinformatic analyses.

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Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Joseph M Negri, D Corey Geer, Steffen Klippel, Nicholas Mitsiades, Robert L Schlossman, Nikhil C Munshi, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  2. Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Ellen Weisberg, Joseph M Negri, D Corey Geer, Steffen Klippel, Nicholas Mitsiades, Robert L Schlossman, Nikhil C Munshi, James D Griffin, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  3. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Douglas W McMillin, Jake Delmore, Ellen Weisberg, Joseph M Negri, D Corey Geer, Steffen Klippel, Robert L Schlossman, Nikhil C Munshi, James D Griffin, Paul G Richardson, Kenneth C Anderson & Constantine S Mitsiades

  4. Boston VA Healthcare System, Boston, Massachusetts, USA

    Nikhil C Munshi

  5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Andrew L Kung

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  1. Douglas W McMillin
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Contributions

D.W.M. conducted experiments, performed analysis and wrote the manuscript; J.D. conducted experiments, performed analysis; E.W. conducted experiments, performed analysis; J.M.N. conducted experiments, performed analysis; D.C.G. conducted experiments, performed analysis; S.K. generated cell lines; N.M. performed analysis; R.L.S. provided primary tissue samples; N.C.M. provided primary tissue samples; A.L.K. performed analysis and participated in writing the manuscript; J.D.G. provided cell lines; P.G.R. provided primary tissue samples; K.C.A. participated in writing the manuscript; C.S.M. performed analysis, wrote manuscript and supervised the project.

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Correspondence to Constantine S Mitsiades.

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Competing interests

D.W.M. has equity in Axios Biosciences. R.L.S. is on the Speakers Bureau for Millennium and Celgene. K.C.A. is a consultant for Millennium, Celgene and Novartis. C.S.M. has received in the past consultant honoraria from Millennium, Novartis, Bristol-Myers Squibb, Merck, Kosan, Pharmion and Centocor, as well as licensing royalties from PharmaMar. He has also received research funding from Amgen, AVEO Pharma, EMD Serono, Sunesis and Gloucester Pharmaceuticals.

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McMillin, D., Delmore, J., Weisberg, E. et al. Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med 16, 483–489 (2010). https://doi.org/10.1038/nm.2112

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