Self-renewal as a therapeutic target in human colorectal cancer

  • Nat Med. 2014 Jan;20(1):29-36. doi: 10.1038/nm.3418.
Antonija Kreso  1 ,  Peter van Galen  2 ,  Nicholas M Pedley  3 ,  Evelyne Lima-Fernandes  4 ,  Catherine Frelin  5 ,  Thomas Davis  6 ,  Liangxian Cao  6 ,  Ramil Baiazitov  6 ,  Wu Du  6 ,  Nadiya Sydorenko  6 ,  Young-Choon Moon  6 ,  Lianne Gibson  3 ,  Yadong Wang  3 ,  Cherry Leung  3 ,  Norman N Iscove  7 ,  Cheryl H Arrowsmith  8 ,  Eva Szentgyorgyi  9 ,  Steven Gallinger  10 ,  John E Dick  11 ,  Catherine A O'Brien  12
Affiliations
  • 1. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 2. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 3. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 4. Structural Genomics Consortium, Toronto, Ontario, Canada.
  • 5. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 6. PTC Therapeutics, South Plainfield, New Jersey, USA.
  • 7. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. [3] Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
  • 8. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Structural Genomics Consortium, Toronto, Ontario, Canada. [3] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 9. Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada.
  • 10. 1] Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. [2] Fred Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
  • 11. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [3].
  • 12. 1] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. [3] Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. [4].
PMID: 24292392 DOI: 10.1038/nm.3418
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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