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Nat Med. 2014 Jan;20(1):29-36. doi: 10.1038/nm.3418. Epub 2013 Dec 1.

Self-renewal as a therapeutic target in human colorectal cancer.

Author information

  • 11] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 2Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 31] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  • 4Structural Genomics Consortium, Toronto, Ontario, Canada.
  • 51] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 6PTC Therapeutics, South Plainfield, New Jersey, USA.
  • 71] 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.
  • 81] 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.
  • 9Department of Pathology, Toronto General Hospital, Toronto, Ontario, Canada.
  • 101] 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.
  • 111] Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [2] Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. [3].
  • 121] 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].

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.

PMID:
24292392
[PubMed - indexed for MEDLINE]
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