Abstract
The growing incidence of non-melanoma skin cancer (NMSC) necessitates a thorough understanding of its primary risk factors, which include exposure to ultraviolet (UV) wavelengths of sunlight and age. Whereas UV radiation (UVR) has long been known to generate photoproducts in genomic DNA that promote genetic mutations that drive skin carcinogenesis, the mechanism by which age contributes to disease pathogenesis is less understood and has not been sufficiently studied. In this review, we highlight studies that have considered age as a variable in examining DNA damage responses in UV-irradiated skin and then discuss emerging evidence that the reduced production of insulin-like growth factor-1 (IGF-1) by senescent fibroblasts in the dermis of geriatric skin creates an environment that negatively impacts how epidermal keratinocytes respond to UVR-induced DNA damage. In particular, recent data suggest that two principle components of the cellular response to DNA damage, including nucleotide excision repair and DNA damage checkpoint signaling, are both partially defective in keratinocytes with inactive IGF-1 receptors. Overcoming these tumor-promoting conditions in aged skin may therefore provide a way to lower aging-associated skin cancer risk, and thus we will consider how dermal wounding and related clinical interventions may work to rejuvenate the skin, re-activate IGF-1 signaling, and prevent the initiation of NMSC.
Highlights
Non-melanoma skin cancers (NMSCs) comprise the most common types of cancers in humans worldwide and originate from keratinocytes within the epidermal layer of the skin
This study found that patients over the age of 50 had more cyclobutane pyrimidine dimers (CPDs)-containing TTT trinucleotides remaining in their epidermal genomic DNA 24 h after UV exposure than subjects under the age of 50, though this difference was no longer present by 48 h
These findings indicate that de-regulation of the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) system during aging may lead to reduced Nucleotide Excision Repair (NER) gene expression that subsequently prevents keratinocytes from efficiently removing UV photoproducts from genomic DNA
Summary
Non-melanoma skin cancers (NMSCs) comprise the most common types of cancers in humans worldwide and originate from keratinocytes within the epidermal layer of the skin. When not properly dealt with, these photoproducts may lead to mutations in genomic DNA that provide a growth advantage to epidermal keratinocytes and initiate a NMSC. The discoveries that the expression of insulin-like growth factor-1 (IGF-1) is lower in the skin of geriatric individuals than in young adults and that the IGF-1/IGF-1 receptor (IGF-1R) system regulates cellular responses to UVB has provided a paradigm shift in our understanding of aging-associated skin carcinogenesis [7,8]. We will review a growing body of literature that supports a role for the insulin-like growth factor (IGF-1) in keratinocyte responses to DNA damage and evidence that this system is de-regulated in geriatric skin. We will discuss clinical interventions that can be employed to counteract this IGF-1-deficiency and the tumor-promoting environment of geriatric skin [9], which may provide a way to reduce skin carcinogenic risk in older patients
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