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A human colon cancer cell capable of initiating tumour growth in immunodeficient mice

Abstract

Colon cancer is one of the best-understood neoplasms from a genetic perspective1,2,3, yet it remains the second most common cause of cancer-related death, indicating that some of its cancer cells are not eradicated by current therapies4,5. 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 potential6,7. 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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Figure 1: Xenografts generated from both bulk and CD133 + colon cancer cells resemble the original patient tumour.
Figure 2: Expression of CD133 in tumour and normal colonic tissue.

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Acknowledgements

We gratefully acknowledge assistance from F. Meng, H. Begley and C. Ash for tissue acquisition, D. Hedley for advice on establishment of the xenograft model, J Wang for assistance with manuscript preparation, and the Dick laboratory members, P. Dirks and D.Hill for comments on the manuscript. We also acknowledge K. So and the University Health Network Pathology Research Program for tissue sectioning and immunohistochemistry. This work was supported by: a clinician-scientist award (C.A.O’B.), and grants (J.E.D.) from the Canadian Institute of Health Research, as well as grants to J.E.D. from Genome Canada through the Ontario Genomics Institute, the Ontario Cancer Research Network with funds from the Province of Ontario, the Leukemia and Lymphoma Society, the National Cancer Institute of Canada with funds from the Canadian Cancer Society and the Terry Fox Foundation, and a Canada Research Chair (J.E.D.). Author Contributions C.A.O'B. planned the project, carried out experimental work, analysed data and prepared the manuscript. A.P. provided pathology analysis. S.G. provided clinical information and human tissues. J.E.D. planned the project, analysed data, and prepared the manuscript.

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Correspondence to John E. Dick.

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Supplementary Figures

This file contains Supplementary Figures 1–4. Supplementary Figure 1: Unfractionated and CD133+ colon cancer cells initiate tumors when transplanted under the renal capsule of NOD/SCID mice. Supplementary Figure 2: Flow cytometric analysis of CD133 and ESA expression. Supplementary Figure 3: Histological examination following injection of CD133- colon cancer cells. Supplementary Figure 4: Analysis of purity following magnetic bead separation (PDF 1021 kb)

Supplementary Methods

This file contains additional details on the methods used in this study. (DOC 28 kb)

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O’Brien, C., Pollett, A., Gallinger, S. et al. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007). https://doi.org/10.1038/nature05372

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