Browsing by Author "Lewis, Davina A."

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    Fibroblast Senescence and Squamous Cell Carcinoma: How wounding therapies could be protective
    (Wolters Kluwer, 2013) Travers, Jeffrey B.; Spandau, Dan F.; Lewis, Davina A.; Machado, Christiane; Kingsley, Melanie; Mousdicas, Nico; Somani, Ally-Khan; Dermatology, School of Medicine
    Background: Squamous cell carcinoma (SCC), which has one of the highest incidences of all cancers in the United States, is an age-dependent disease, with the majority of these cancers diagnosed in people age 70 and older. Recent findings have led to a new hypothesis on the pathogenesis of SCC. Objectives: To evaluate the potential of preventive therapies to reduce the incidence of SCC in at-risk geriatric patients. Materials and methods: Survey of current literature on wounding therapies to prevent SCCs. Results: This new hypothesis of SCC photocarcinogenesis states that senescent fibroblasts accumulate in the dermis, resulting in a reduction in dermal insulin-like growth factor-1 (IGF-1) expression. This lack of IGF-1 expression sensitizes epidermal keratinocytes to fail to suppress ultraviolet light B (UVB)-induced mutations, leading to increased proclivity to photocarcinogenesis. Recent evidence suggests that dermal wounding therapies, specifically dermabrasion and fractionated laser resurfacing, can decrease the proportion of senescent dermal fibroblasts, increase dermal IGF-1 expression, and correct the inappropriate UVB response found in geriatric skin, protecting geriatric keratinocytes from UVB-induced SCC initiation. Conclusions: In this review, we will discuss the translation of pioneering basic science results implicating commonly used dermal fibroblast rejuvenation procedures as preventative treatments for SCC.
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    Insulin‐like growth factor‐1 receptor regulates repair of ultraviolet B‐induced DNA damage in human keratinocytes in vivo
    (Wiley, 2016-10) Loesch, Mathew M.; Collier, Ann E.; Southern, David H.; Ward, Rachel E.; Tholpady, Sunil S.; Lewis, Davina A.; Travers, Jeffrey B.; Spandau, Dan F.; Dermatology, School of Medicine
    The activation status of the insulin‐like growth factor‐1 receptor (IGF‐1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF‐1 expression resulting in an aberrant IGF‐1R‐dependent UVB response which contributes to the development of aging‐associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB‐induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF‐1R activation influences DNA damage repair in UVB‐irradiated keratinocytes. Specifically, in the absence of IGF‐1R activation, the rate of DNA damage repair following UVB‐irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF‐1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF‐1R also exhibited lower steady‐state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB‐induced DNA repair in geriatric keratinocytes is due in part to silenced IGF‐1R activation in geriatric skin and provide a mechanism for how the IGF‐1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients., IGF‐1R is necessary for optimal repair of UVB‐induced DNA damage in keratinocytes.Novel separation technique allows study specifically in basal layer keratinocytes.IGF‐1R activation enhances the expression of nucleotide excision repair genes.
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    Randomized controlled trial of fractionated laser resurfacing on aged skin as prophylaxis against actinic neoplasia
    (The American Society for Clinical Investigation, 2021) Spandau, Dan F.; Chen, Roy; Wargo, Jeffrey J.; Rohan, Craig A.; Southern, David; Zhang, Angela; Loesch, Mathew; Weyerbacher, Jonathan; Tholpady, Sunil S.; Lewis, Davina A.; Kuhar, Matthew; Tsai, Kenneth Y.; Castellanos, Amber J.; Kemp, Michael G.; Markey, Michael; Cates, Elizabeth; Williams, Amy R.; Knisely, Christina; Bashir, Sabina; Gabbard, Ryan; Hoopes, Robert; Travers, Jeffrey B.; Biochemistry and Molecular Biology, School of Medicine
    BACKGROUND: The loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC. METHODS: A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. RESULTS: Xenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs). CONCLUSION: The elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations.