Actinic keratosis modelling in mice: A translational study

Abstract

BackgroundActinic keratoses (AK) are pre-malignant cutaneous lesions caused by prolonged exposure to ultraviolet radiation. As AKs lesions are generally accepted to be the initial lesions in a disease continuum that progresses to squamous cell carcinoma (SCC), AK lesions have to be treated. They are also the second most common reason for visits to the dermatologist. Several treatments are available but their efficacy still needs to be improved. The UV-B-induced KA lesion mouse model is used in preclinical studies to assess the efficacy of novel molecules, even though it is often more representative of advanced AK or SCC.ObjectivesHere we report on a translational study, comparing the various stages of AK development in humans and in the UV-B irradiated mouse model, as well as the optimization of photograph acquisition of AK lesions on mouse skin.MethodsHuman and mouse skin lesions were analysed by histology and immunohistochemistry. Mouse lesions were also assessed using a digital dermatoscope.ResultsAn histological and phenotypic analysis, including p53, Ki67 and CD3 expression detection, performed on human and mouse AK lesions, shows that overall AK modelling in mice is relevant in the clinical situation. Some differences are observed, such as disorganization of keratinocytes of the basal layer and a number of atypical nuclei which are more numerous in human AK, whereas much more pronounced acanthosis is observed in skin lesion in mice. Thanks to this translational study, we are able to select appropriate experimental conditions for establishing either early or advanced stage AK or an SCC model. Furthermore, we optimized photograph acquisition of AK lesions on mouse skin by using a digital dermatoscope which is also used in clinics and allows reproducible photograph acquisition for further reliable assessment of mouse lesions. Use of this camera is illustrated through a pharmacological study assessing the activity of CARAC®.ConclusionThese data demonstrate that this mouse model of UV-B-induced skin lesions is predictive for the identification of novel therapeutic treatments for both early and advanced stages of the disease.

Painless Photodynamic Therapy Triggers Innate and Adaptive Immune Responses in a Murine Model of UV‐induced Squamous Skin Pre‐cancer

“…The chronic UV exposure was incrementally increased from 90 to 180 mJ cm −2 s −1 , resulting in a gradual appearance of AK lesions that morphologically and histologically resembled actinic keratosis in humans (Fig. 1A and B) (44,45). Histological and preneoplastic characteristics of the AK lesions were confirmed by Haematoxylin/Eosin (H&E) staining (Fig.…”

“…Studies published by several groups including our own have shown that AK can be modeled in mice using a prolonged UVB-exposure regimen, and that the morphology and histology of the lesions in mice resemble those in humans (44,45). Based on these observations, SKH-1 mice were subjected to a 20-week UVB-exposure regimen, as described in the methods section (44,48).…”

Characterization of Permeability Barrier Dysfunction in a Murine Model of Cutaneous Field Cancerization Following Chronic UV-B Irradiation: Implications for the Pathogenesis of Skin Cancer

“…Although this reconstructed human epidermis from UV-B-irradiated keratinocytes displayed a thinner stratum corneum compared to normal reconstructed human epidermis, a reactive epidermis to chronic UV-B irradiation, characterized by orthokeratotic hyperplasia with hypergranulosis and PCNA and PIPs overexpression, together with several patches of incidental AKs or in situ SCCs associated with hypogranulosis were the main features in our murine model of skin with CFC. These differences in the epidermal architecture can be explained if we consider that, similarly to other published murine models of AKs and NMSC [22,30,31], our model in SKH1 mice represents a better approach to the complexity of the skin with CFC than in vitro models, including reconstructed human epidermis.…”

“…Due to the proviral insertion of the murine leukemia virus at Hr locus, which leads to a recessive hypomorphic mutation, these mice do not develop fur but, contrary to nude mice, they are still immunocompetent [29]. According to Pillon et al, as most AKs and SCCs arise in elderly individuals who show structural differences in the skin with respect to younger individuals, SKH1 aged mice might be used to optimize their mouse model of AK [30]. Another reason to use SKH1 aged mice was because the skin barrier differs depending on age, showing an impairment in the elderly [13].…”

Peeling with 70% glicolic acid followed by 5% 5‐fluorouracil as well as 5% 5‐fluorouracil cream are effective methods for the treatment of actinic keratoses on upper limbs: A randomized clinical trial

“…Currently, there are several treatment options available, but their efficacy still needs to be improved 3 . Basically, these treatments range from topical medications to light‐based therapies and procedures.…”