1. Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, M5G 1L7, Canada
2. Department of Pathology and Laboratory Medicine,
3. Center for Cancer Genetics-Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
4. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada

Correspondence to: John E. Dick^1,4 Correspondence and requests for materials should be addressed to J.E.D. (Email: jdick@uhnres.utoronto.ca).

Abstract

Colon cancer is one of the best-understood neoplasms from a genetic perspective^{1, 2, 3}, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies^{4, 5}. What has yet to be established is whether every colon cancer cell possesses the potential to initiate and sustain tumour growth, or whether the tumour is hierarchically organized so that only a subset of cells—cancer stem cells—possess such potential^{6, 7}. Here we use renal capsule transplantation in immunodeficient NOD/SCID mice to identify a human colon cancer-initiating cell (CC-IC). Purification experiments established that all CC-ICs were CD133⁺; the CD133^- cells that comprised the majority of the tumour were unable to initiate tumour growth. We calculated by limiting dilution analysis that there was one CC-IC in 5.7  10⁴ unfractionated tumour cells, whereas there was one CC-IC in 262 CD133⁺ cells, representing >200-fold enrichment. CC-ICs within the CD133⁺ population were able to maintain themselves as well as differentiate and re-establish tumour heterogeneity upon serial transplantation. The identification of colon cancer stem cells that are distinct from the bulk tumour cells provides strong support for the hierarchical organization of human colon cancer, and their existence suggests that for therapeutic strategies to be effective, they must target the cancer stem cells.

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