Self-renewal as a therapeutic target in human colorectal cancer

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bromodeoxyuridine
  • Cell Line, Tumor
  • Colorectal Neoplasms / drug therapy*
  • Flow Cytometry
  • Genetic Vectors / genetics
  • Heterocyclic Compounds, 2-Ring / pharmacology*
  • Heterocyclic Compounds, 2-Ring / therapeutic use
  • Humans
  • Luciferases
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Recurrence, Local / metabolism*
  • Neoplastic Stem Cells / metabolism*
  • Polycomb Repressive Complex 1 / antagonists & inhibitors
  • Polycomb Repressive Complex 1 / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Thiazoles / pharmacology*
  • Thiazoles / therapeutic use


  • BMI1 protein, human
  • Heterocyclic Compounds, 2-Ring
  • PTC-209
  • RNA, Small Interfering
  • Thiazoles
  • Luciferases
  • Polycomb Repressive Complex 1
  • Bromodeoxyuridine