Non-melanoma skin cancer is a disease primarily afflicting geriatric patients as evidenced by the fact that 80% of all non-melanoma skin cancers are diagnosed in patients over the age of 60 years. As such, geriatric skin responds to cancer-inducing UVB irradiation in a manner that allows the establishment of tumor cells. While the correlation between aged epidermis and skin cancer is obvious, the mechanism responsible for this relationship remains obscure. Recent in vitro evidence as well as epidemiological data suggests one possible mechanism may involve alterations in the insulin-like growth factor-1 receptor (IGF-1R) signaling network. Using normal human keratinocytes grown in vitro, activated IGF-1Rs protect keratinocytes from UVB-induced apoptosis;however, while UVB-irradiated keratinocytes with activated IGF-1Rs survive, they are incapable of further cellular replication, in fact they are senescent. The critically important observation was that in the absence of IGF-1R activation, keratinocytes are more sensitive to UVB-induced apoptosis, but the keratinocytes that do survive retain the capacity to proliferate. In the skin, keratinocytes express the IGF-1R but they do not synthesize IGF-1. Dermal fibroblasts support the proliferation of keratinocytes in the epidermis by secreting IGF-1. Interestingly, as dermal fibroblasts age, their capacity to produce IGF-1 is severely diminished;therefore, in aged skin keratinocytes are provided with a reduced supply of IGF-1 and a concomitant reduction in IGF-1R activation. We have demonstrated that geriatric skin responds to UVB irradiation in a manner that could lead to initiated carcinogenic keratinocytes. This inappropriate UVB response can be corrected by treatment with exogenous IGF-1. Furthermore, we have shown that treatment of geriatric skin with ablative dermal rejuvenation therapies can re-establish youthful IGF-1 levels and subsequently reinstate the appropriate UVB response on sun-protected skin. In this proposal, we will use non- ablative dermal rejuvenation therapies to restore IGF-1 expression on sun-exposed geriatric skin to the levels seen in young adult skin and determine if these therapies can restore the appropriate UVB response. In addition, we will test the ability of non-ablative dermal rejuvenation therapies to protect against the formation of actinic keratoses and non-melanoma skin cancer. Finally, we will use human skin xenografts grown on immunodeficient mice to establish that the inhibition of the IGF-1R on epidermal keratinocytes sensitizes the keratinocytes to the development of UVB-induced actinic neoplasia. These studies will have a major impact on the treatment of NMSC by establishing a novel anti-carcinogenic role for dermal wounding. Furthermore, the data from these studies will confirm a new paradigm defining the mechanism of age-associated skin cancer.
The goal of the project described in this proposal is to determine whether wounding therapies, currently in use as cosmetic procedures, can prevent the occurrence of non-melanoma skin cancers in geriatric patients. Additionally, animal studies have been designed to test the hypothesis that geriatric skin is predisposed to develop skin cancer.
|Fahy, Katherine; Liu, Langni; Rapp, Christine M et al. (2016) UVB-generated Microvesicle Particles: A Novel Pathway by Which a Skin-specific Stimulus Could Exert Systemic Effects. Photochem Photobiol :|
|Loesch, Mathew M; Collier, Ann E; Southern, David H et al. (2016) Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes inÂ vivo. Mol Oncol 10:1245-54|
|Krbanjevic, Aleksandar; Travers, Jeffrey B; Spandau, Dan F (2016) How Wounding via Lasers Has Potential Photocarcinogenic Preventative Effects via Dermal Remodeling. Curr Dermatol Rep 5:222-227|
|Ferracini, Matheus; Sahu, Ravi P; Harrison, Kathleen A et al. (2015) Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands. J Invest Dermatol 135:321-3|
|Collier, Ann E; Wek, Ronald C; Spandau, Dan F (2015) Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response. J Invest Dermatol 135:2502-11|
|Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A et al. (2014) Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Res 74:7069-78|