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.TRIAL REGISTRATION ClinicalTrials.gov (NCT03906253).FUNDING National Institutes of Health, Veterans Administration.
Dan F. Spandau, Roy Chen, Jeffrey J. Wargo, Craig A. Rohan, David Southern, Angela Zhang, Mathew Loesch, Jonathan Weyerbacher, Sunil S. Tholpady, Davina A. Lewis, Matthew Kuhar, Kenneth Y. Tsai, Amber J. Castellanos, Michael G. Kemp, Michael Markey, Elizabeth Cates, Amy R. Williams, Christina Knisely, Sabina Bashir, Ryan Gabbard, Robert Hoopes, Jeffrey B. Travers