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Self-renewal as a therapeutic target in human colorectal cancer

Nature Medicine volume 20, pages 29–36 (2014)Cite this article

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Abstract

Tumor recurrence following treatment remains a major clinical challenge. Evidence from xenograft models and human trials indicates selective enrichment of cancer-initiating cells (CICs) in tumors that survive therapy. Together with recent reports showing that CIC gene signatures influence patient survival, these studies predict that targeting self-renewal, the key 'stemness' property unique to CICs, may represent a new paradigm in cancer therapy. Here we demonstrate that tumor formation and, more specifically, human colorectal CIC function are dependent on the canonical self-renewal regulator BMI-1. Downregulation of BMI-1 inhibits the ability of colorectal CICs to self-renew, resulting in the abrogation of their tumorigenic potential. Treatment of primary colorectal cancer xenografts with a small-molecule BMI-1 inhibitor resulted in colorectal CIC loss with long-term and irreversible impairment of tumor growth. Targeting the BMI-1–related self-renewal machinery provides the basis for a new therapeutic approach in the treatment of colorectal cancer.

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Figure 1: BMI-1 knockdown impairs human colorectal cancer cell growth.
Figure 2: Attenuated proliferation and increased apoptosis upon BMI-1-KD.
Figure 3: BMI-1 knockdown reduces the frequency of self-renewing colorectal CICs.
Figure 4: BMI-1 inhibitor reduces BMI-1 levels and is not overtly toxic.
Figure 5: BMI-1 inhibitor permanently reduces colorectal CICs.
Figure 6: Therapeutic targeting of the BMI-1–related self-renewal machinery.

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References

  1. Dick, J.E. Stem cell concepts renew cancer research. Blood 112, 4793–4807 (2008).

    Article  PubMed  CAS  Google Scholar 

  2. O'Brien, C.A., Pollett, A., Gallinger, S. & Dick, J.E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).

    Article  PubMed  CAS  Google Scholar 

  3. Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer–initiating cells. Nature 445, 111–115 (2007).

    Article  PubMed  CAS  Google Scholar 

  4. Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl. Acad. Sci. USA 104, 10158–10163 (2007).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Bao, S. et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756–760 (2006).

    Article  PubMed  CAS  Google Scholar 

  6. Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl. Cancer Inst. 100, 672–679 (2008).

    Article  PubMed  CAS  Google Scholar 

  7. Tehranchi, R. et al. Persistent malignant stem cells in del(5q) myelodysplasia in remission. N. Engl. J. Med. 363, 1025–1037 (2010).

    Article  PubMed  CAS  Google Scholar 

  8. Majeti, R. et al. CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138, 286–299 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Todaro, M. et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell 1, 389–402 (2007).

    Article  PubMed  CAS  Google Scholar 

  10. Kreso, A. et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 339, 543–548 (2013).

    Article  PubMed  CAS  Google Scholar 

  11. Singh, S.K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).

    Article  PubMed  CAS  Google Scholar 

  12. Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. & Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 100, 3983–3988 (2003).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. O'Brien, C.A. et al. ID1 and ID3 regulate the self-renewal capacity of human colon cancer-initiating cells through p21. Cancer Cell 21, 777–792 (2012).

    Article  PubMed  CAS  Google Scholar 

  14. Park, I.K. et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423, 302–305 (2003).

    Article  PubMed  CAS  Google Scholar 

  15. Lessard, J. & Sauvageau, G. Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423, 255–260 (2003).

    Article  PubMed  CAS  Google Scholar 

  16. Molofsky, A.V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sparmann, A. & van Lohuizen, M. Polycomb silencers control cell fate, development and cancer. Nat. Rev. Cancer 6, 846–856 (2006).

    Article  PubMed  CAS  Google Scholar 

  18. Sauvageau, M. & Sauvageau, G. Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 7, 299–313 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Sangiorgi, E. & Capecchi, M.R. Bmi1 is expressed in vivo in intestinal stem cells. Nat. Genet. 40, 915–920 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Tian, H. et al. A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478, 255–259 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Bruggeman, S.W. et al. Bmi1 controls tumor development in an Ink4a/Arf-independent manner in a mouse model for glioma. Cancer Cell 12, 328–341 (2007).

    Article  PubMed  CAS  Google Scholar 

  22. Leung, C. et al. Bmi1 is essential for cerebellar development and is overexpressed in human medulloblastomas. Nature 428, 337–341 (2004).

    Article  PubMed  CAS  Google Scholar 

  23. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lukacs, R.U., Memarzadeh, S., Wu, H. & Witte, O.N. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell 7, 682–693 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Dovey, J.S., Zacharek, S.J., Kim, C.F. & Lees, J.A. Bmi1 is critical for lung tumorigenesis and bronchioalveolar stem cell expansion. Proc. Natl. Acad. Sci. USA 105, 11857–11862 (2008).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Chiba, T. et al. The polycomb gene product BMI1 contributes to the maintenance of tumor-initiating side population cells in hepatocellular carcinoma. Cancer Res. 68, 7742–7749 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Abdouh, M. et al. BMI1 sustains human glioblastoma multiforme stem cell renewal. J. Neurosci. 29, 8884–8896 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Kim, J.H. et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett. 203, 217–224 (2004).

    Article  PubMed  CAS  Google Scholar 

  29. Li, D.W. et al. Expression level of Bmi-1 oncoprotein is associated with progression and prognosis in colon cancer. J. Cancer Res. Clin. Oncol. 136, 997–1006 (2010).

    Article  PubMed  CAS  Google Scholar 

  30. Du, J., Li, Y., Li, J. & Zheng, J. Polycomb group protein Bmi1 expression in colon cancers predicts the survival. Med. Oncol. 27, 1273–1276 (2010).

    Article  PubMed  CAS  Google Scholar 

  31. Tateishi, K. et al. Dysregulated expression of stem cell factor Bmi1 in precancerous lesions of the gastrointestinal tract. Clin. Cancer Res. 12, 6960–6966 (2006).

    Article  PubMed  CAS  Google Scholar 

  32. Vermeulen, L. et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat. Cell Biol. 12, 468–476 (2010).

    Article  PubMed  CAS  Google Scholar 

  33. Dylla, S.J. et al. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS ONE 3, e2428 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Wang, J.C. Evaluating therapeutic efficacy against cancer stem cells: new challenges posed by a new paradigm. Cell Stem Cell 1, 497–501 (2007).

    Article  PubMed  CAS  Google Scholar 

  35. Kvinlaug, B.T. & Huntly, B.J. Targeting cancer stem cells. Expert Opin. Ther. Targets 11, 915–927 (2007).

    Article  PubMed  CAS  Google Scholar 

  36. Trumpp, A. & Wiestler, O.D. Mechanisms of disease: cancer stem cells—targeting the evil twin. Nat. Clin. Pract. Oncol. 5, 337–347 (2008).

    Article  PubMed  CAS  Google Scholar 

  37. Liu, S. & Wicha, M.S. Targeting breast cancer stem cells. J. Clin. Oncol. 28, 4006–4012 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Diehn, M., Cho, R.W. & Clarke, M.F. Therapeutic implications of the cancer stem cell hypothesis. Semin. Radiat. Oncol. 19, 78–86 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Kreso, A. & O'Brien, C.A. Colon cancer stem cells. Curr. Protoc. Stem Cell Biol. 7, 3.1 (2008).

    Google Scholar 

  40. Hu, Y. & Smyth, G.K. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J. Immunol. Methods 347, 70–78 (2009).

    Article  PubMed  CAS  Google Scholar 

  41. Amendola, M., Venneri, M.A., Biffi, A., Vigna, E. & Naldini, L. Coordinate dual-gene transgenesis by lentiviral vectors carrying synthetic bidirectional promoters. Nat. Biotechnol. 23, 108–116 (2005).

    Article  PubMed  CAS  Google Scholar 

  42. Voorhoeve, P.M. & Agami, R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell 4, 311–319 (2003).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank R. Lopez and P. Lo from the Animal Research Centre, University Health Network and A. Khandani, P. Penttila, and S. Zhao from the Sickkids Flow Cytometry facility for their skillful assistance. We are grateful to all members of the Dick lab, especially M. Anders, E. Laurenti, N. Mbong, S. Doulatov, M. Milyavsky and F. Notta, as well as C. Gedye and J. Wang for their advice and critical comments. We thank E. Lechman (University Health Network, Toronto), J. Moffat (University of Toronto) and T. Chiba (Chiba University) for lentiviral vectors expressing shRNAs to BMI1. We also thank members from the Department of Pathology (Toronto General Hospital), including F. Meng, M. Sukhram, V. Son, H. Begley and P. Shaw, for providing colon cancer samples. This work was supported by funds to PTC Therapeutics from the Wellcome Trust and to J.E.D. from Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research and a Summit Award with funds from the province of Ontario, the Canadian Institutes for Health Research, a Canada Research Chair, the Princess Margaret Hospital Foundation and funds to E.L.-F. by Fonds National de la Recherche, Luxembourg and the Marie Curie Actions of the European Commission (FP7-COFUND, PDR 2012-2 4735314). This research was funded in part by the Ontario Ministry of Health and Long Term Care (OMOHLTC). The views expressed do not necessarily reflect those of the OMOHLTC.

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Author notes

  1. John E Dick and Catherine A O'Brien: These authors contributed equally to this work.

Authors and Affiliations

  1. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada

    Antonija Kreso, Peter van Galen, Nicholas M Pedley, Catherine Frelin, Lianne Gibson, Yadong Wang, Cherry Leung, Norman N Iscove, Cheryl H Arrowsmith, John E Dick & Catherine A O'Brien

  2. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    Antonija Kreso & John E Dick

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Nicholas M Pedley, Lianne Gibson, Yadong Wang, Cherry Leung & Catherine A O'Brien

  4. Structural Genomics Consortium, Toronto, Ontario, Canada

    Evelyne Lima-Fernandes & Cheryl H Arrowsmith

  5. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Catherine Frelin, Norman N Iscove & Cheryl H Arrowsmith

  6. PTC Therapeutics, South Plainfield, New Jersey, USA

    Thomas Davis, Liangxian Cao, Ramil Baiazitov, Wu Du, Nadiya Sydorenko & Young-Choon Moon

  7. Department of Immunology, University of Toronto, Toronto, Ontario, Canada

    Norman N Iscove

  8. Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada

    Eva Szentgyorgyi

  9. Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada

    Steven Gallinger & Catherine A O'Brien

  10. Fred Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Steven Gallinger

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Contributions

A.K., C.A.O., J.E.D. designed the study. A.K., P.v.G., N.M.P., E.L.-F., C.F., L.G., Y.W., C.L. and C.A.O. performed experiments. N.N.I. and C.H.A. supervised specific experiments. T.D., L.C., R.B., W.D., N.S. and Y.-C.M. provided BMI-1 inhibitor and performed experiments. E.S. assessed tumor histology. S.G. provided tumor specimens. A.K., P.v.G., C.A.O. and J.E.D. analyzed and interpreted data. P.v.G., C.A.O. and J.E.D. revised the paper. A.K. wrote the paper. J.E.D. supervised the study.

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Correspondence to John E Dick.

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Kreso, A., van Galen, P., Pedley, N. et al. Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 20, 29–36 (2014). https://doi.org/10.1038/nm.3418

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