Self-renewal as a therapeutic target in human colorectal cancer
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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Treatment of patient-derived CRC xenografts with a small molecule inhibitor of BMI-1 resulted in loss of colorectal CSCs and long-term impairment of tumor growth.
“For instance, treatment of patient-derived CRC xenografts with a small molecule inhibitor of BMI-1 (a subunit of the Polycomb Repressive Complex 1 that functions as an epigenetic chromatin modifier) resulted in loss of colorectal CSCs and long-term impairment of tumor growth [203].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [203]
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- Authors
- Kreso, A., van Galen, P., Pedley, N. M., Lima-Fernandes, E., Frelin, C., Davis, T., Cao, L., Baiazitov, R., Du, W., Sydorenko, N., Moon, Y.-C., Gibson, L., Wang, Y., Leung, C., Iscove, N. N., Arrowsmith, C. H., Szentgyorgyi, E., Gallinger, S., Dick, J. E., & O'Brien, C. A.
- Affiliations
- University Health Network (CA)
- PTC Therapeutics (United States) (US)
- Toronto General Hospital (CA)
- Corresponding author
- Dick, John E
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-12-01
- Volume
- 20
- Issue
- 1
- Pages
- 29-36
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2120997349
- Cited by
- 500
- References
- 42
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 24 · 2023: 28 · 2022: 40 · 2021: 53 · 2020: 38 · 2019: 40 · 2018: 44 · 2017: 57 · 2016: 59 · 2015: 61 · 2014: 35 · 2013: 1
- FWCI
- 27.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (092809, 092687)
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- colorectal cancer, cancer stem cells, BMI1, self-renewal, small molecule inhibitors, tumor recurrence, tumorigenicity, therapeutic target
- MeSH terms
- Animals, Bromodeoxyuridine, Flow Cytometry, Genetic Vectors, Heterocyclic Compounds, 2-Ring, Humans, Luciferases, Neoplasm Recurrence, Local, Thiazoles, Neoplastic Stem Cells, Blotting, Western, Colorectal Neoplasms, Mice, SCID, Mice, Inbred NOD, RNA Interference, RNA, Small Interfering, Cell Line, Tumor, Polycomb Repressive Complex 1
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