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Cell. 2016 Aug 25;166(5):1132-1146.e7. doi: 10.1016/j.cell.2016.07.045.

Multi-organ Mapping of Cancer Risk.

Author information

1
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
2
Department of Computational Biology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
3
Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
4
Department of Pathology & Immunology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
5
Developmental Biology, Regenerative Medicine, and Stem Cell, Division of Pediatric Surgery, Children's Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, CA 90027, USA.
6
Hartwell Center, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
7
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
8
Department of Biostatistics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. Electronic address: arzu.onar@stjude.org.
9
Department of Oncology and CRUK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, England. Electronic address: richard.gilbertson@cruk.cam.ac.uk.

Abstract

Cancers are distributed unevenly across the body, but the importance of cell intrinsic factors such as stem cell function in determining organ cancer risk is unknown. Therefore, we used Cre-recombination of conditional lineage tracing, oncogene, and tumor suppressor alleles to define populations of stem and non-stem cells in mouse organs and test their life-long susceptibility to tumorigenesis. We show that tumor incidence is determined by the life-long generative capacity of mutated cells. This relationship held true in the presence of multiple genotypes and regardless of developmental stage, strongly supporting the notion that stem cells dictate organ cancer risk. Using the liver as a model system, we further show that damage-induced activation of stem cell function markedly increases cancer risk. Therefore, we propose that a combination of stem cell mutagenesis and extrinsic factors that enhance the proliferation of these cell populations, creates a "perfect storm" that ultimately determines organ cancer risk. VIDEO ABSTRACT.

PMID:
27565343
PMCID:
PMC5067024
DOI:
10.1016/j.cell.2016.07.045
[Indexed for MEDLINE]
Free PMC Article

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