Cellular senescence in naevi and immortalisation in melanoma: a role for p16?
Open accessAbstract
Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growth-phase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.
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Hallmarks of senescent cells were subsequently identified in dermal premalignant lesions, specifically human melanocytic naevi.
“Hallmarks of senescent cells were subsequently identified in dermal premalignant lesions, specifically human melanocytic naevi 81,82 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [82]
Benign melanocytic lesions, which are melanoma precursors in humans, express high p16 and are an in vivo example of OIS.
“Benign melanocytic lesions, which are melanoma precursors in humans, express high p16 and are an in vivo example of OIS [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [55]
N-RAS- or B-RAF-activating mutations are commonly found in benign melanocytic nevi that show features of senescence, such as elevated p16 levels, but that do not express appreciable levels of ARF or p53.
“For example, N-RAS- or B-RAF-activating mutations are commonly found in benign melanocytic nevi that show features of senescence, such as elevated p16 levels, but that do not express appreciable levels of ARF or p53 [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [55]
The ARF locus is more commonly deleted or silenced than mutated in melanoma.
“Indeed, its locus is more commonly deleted or silenced than mutated in melanoma, the more malignant later stage of disease [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [55]
Developmental senescent cells express p21WAF1/Cip1 but not p16INK4a, while the reverse is observed in melanocytic nevi.
“For example, developmental senescent cells express p21WAF1/Cip1 but not p16INK4a9,10, while the reverse is observed in melanocytic nevi36,37.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [37]
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- Authors
- Gray-Schopfer, V. C., Cheong, S. C., Chong, H., Chow, J., Moss, T., Abdel-Malek, Z. A., Marais, R., Wynford-Thomas, D., & Bennett, D. C.
- Affiliations
- St George's, University of London (GB)
- University of London (GB)
- St George's Hospital (GB)
- Institute of Cancer Research (GB)
- Corresponding author
- Bennett, D C
- Venue
- British Journal of Cancer
- Published
- 2006-08
- Volume
- 95
- Issue
- 4
- Pages
- 496-505
- ISSN
- 0007-0920 (ISSN-L)
- 1532-1827
- PMC
- PMC2360676
- OpenAlex
- W2097010979
- Cited by
- 394
- References
- 48
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 16 · 2020: 16 · 2019: 15 · 2018: 16 · 2017: 16 · 2016: 18 · 2015: 22 · 2014: 15 · 2013: 24 · 2012: 25
- FWCI
- 21.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- British Journal of Cancer (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- European Commission
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cellular senescence, melanoma, melanocytic naevi, p16, CDKN2A, retinoblastoma pathway, p53, p21, telomerase, dysplastic naevi, vertical growth phase melanoma, senescence escape
- MeSH terms
- Cell Survival, Cells, Cultured, Humans, Melanocytes, Melanoma, Nevus, Skin Neoplasms, Tumor Suppressor Protein p53, Cellular Senescence, Disease Progression, Cyclin-Dependent Kinase Inhibitor p16, Proto-Oncogene Proteins B-raf, Cyclin-Dependent Kinase Inhibitor p21
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