Key Points
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Cancer is not a cell-autonomous disease, but involves disruption of the complex system of controls exerted by the local microenvironment, as well as hormonal or immune-system components produced by the whole organism.
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Cancer, like any other tissue that is capable of regeneration or progressive growth, must have cells with self-renewal capacity and a hierarchical architecture.
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Although many tumours contain cells with the characteristics of stem cells, the identity of the normal cells that acquire the first genetic hits leading to initiation of carcinogenesis has remained elusive. Although expression of stem-cell markers might reflect the tumour cell of origin, it remains possible that these markers are induced by the oncogenic events that occur after the initiation of neoplastic growth.
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It is likely that there is a continuum of target cells for carcinogenesis, and that combinations of the particular cells in which mutations occur, as well as the specific genes altered, are the main determinants of cell fate and malignant potential.
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Tumour promoters, which are not in themselves mutagenic, might affect the specific choice of initiated cell that forms a visible lesion and allows the selection of particular target cells.
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Oncogenic events allow proliferation and self-renewal genetic programmes to be reconciled within the developing tumour.
Abstract
Tumour architecture mimics many of the features of normal tissues, with a cellular hierarchy that regulates the balance between cell renewal and cell death. Although many tumours contain cells with the characteristics of stem cells, the identity of the normal cells that acquire the first genetic hits leading to initiation of carcinogenesis has remained elusive. Identification of the primary cell of origin of cancers and the mechanisms that influence cell-fate decisions will be crucial for the development of novel non-toxic therapies that influence tumour-cell behaviour.
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Acknowledgements
Work in the authors' laboratory is supported by a grant from the National Cancer Institute's Mouse Models of Human Cancer Consortium. We would like to acknowledge numerous colleagues for useful discussions and comments on the manuscript. J.P.-L is the recipient of a Fellowship support of the 'Ministerio de Educacion y Ciencia' of Spain. A.B. would like to acknowledge the continued encouragement and support of B. Bass Bakar and S. Lloyd.
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Glossary
- BULGE
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Region of the outer root sheath in the hair follicle that lies adjacent to the insertion of the arrector pili muscle, and where the stem cells reside.
- ASYMMETRICAL CELL DIVISION
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Mitosis in which one stem cell leads to one new daughter stem cell and another cell that differentiates along a particular lineage.
- SYMMETRICAL CELL DIVISION
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Mitosis in which one stem cell leads to two identical stem cells or two identical more-differentiated cells.
- TRANSIT AMPLIFYING CELLS
-
Skin-cell population defined as cells that are able to divide only 3–5 times before all of their daughters terminally differentiate.
- HYPERPLASIA
-
Enlargement of a tissue or organ due to an increase in the number of cells without cytological or architectural tissue abnormalities. This is normally reversible after the stimulus disappears.
- DYSPLASIA
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Premalignant lesion that shows signs of increased proliferation, as well as cytological or architectural tissue abnormalities. It can be reversible when the stimulus ceases.
- SKIN PAPILLOMA
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Benign tumour showing increased proliferation and a high degree of differentiation. The proliferating cells do not penetrate the epithelial basement membrane.
- SQUAMOUS INVASIVE CARCINOMA
-
Malignant epithelial lesion with many cytological and architectural tissue abnormalities; the cells have penetrated the epithelial basement membrane and invaded the dermis.
- SPINDLE CARCINOMA
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Poorly differentiated carcinoma variant, which is highly aggressive, and in which a high proportion of the cells resemble fibroblasts.
- TUMOUR INITIATION
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The first step in the process of transformation, usually involving a mutation that converts the target epidermal cell into a latent initiated cell that is capable of undergoing clonal selection to become a tumour.
- TUMOUR PROMOTER
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An exogenously applied molecule or agent (or endogenous growth factor) that stimulates the growth and selection of the initiated cell that carries the first mutation.
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Perez-Losada, J., Balmain, A. Stem-cell hierarchy in skin cancer. Nat Rev Cancer 3, 434–443 (2003). https://doi.org/10.1038/nrc1095
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DOI: https://doi.org/10.1038/nrc1095