Abstract 18: Targeted epidermal ablation of EGFR causes local and systemic inflammation
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AbstractEGFR is overexpressed or mutated in a variety of malignancies, and it plays a fundamental role in tumor development and progression, in the angiogenetic process and in the metastatic spread of tumors. As a result investigators have developed approaches to inhibit EGFR activation, with the aim of blocking tumor growth and invasion. The most common adverse effect seen with EGFR inhibition therapy is a pronounced skin inflammatory response (papulopustular rash) that can affect different areas of the body with variable severity. Interestingly, in vitro and in vivo experiments demonstrate that the pharmacological blockade of EGFR or ERK1/2, induces chemokine expression in epidermal keratinocytes and in turn leads to worsening of skin inflammatory conditions. Recent findings suggest a link between chemokine expression and EGFR status in the skin lesions of patients undergoing EGFR therapy and during tumor progression in BCC (basal cell carcinoma) and SCC (squamous cell carcinoma) skin lesions. Given these previous findings we believe that the study of the regulatory functions of the EGFR-ERK1/2 pathway on skin inflammatory mediators will help in understanding not only the adverse effect of this broad class of antitumor drugs but will possibly help to understand if and how they can modify the tumor microenvironment. In this study a mouse model was developed to better characterize the role of EGFR in the control of skin inflammation. By crossing Keratin 5 driven Cre recombinase transgenics with EGFR floxed mice, EGFR was ablated in the epidermis. During the first week of life, double transgenics started to display a strong skin phenotype with aberrant hair growth. During the following weeks the skin of these mice became progressively more inflamed with abundant neutrophilic infiltrate, scaly, dry and less elastic and underwent cycles of hair growth and hair loss. Double transgenic mice experienced a strong pruritus through their entire life, and their scratching behavior caused skin erosions. Tissue samples isolated from skin of adult double transgenics contained high levels of CD45 antigen and increased mRNA levels of a subset of inflammatory mediators namely CCL17, CCL20, CCL2, TNF-, IL-6, IL-17, IL-18, and G-CSF. Targeted knockout mice also displayed hematological abnormalities with a higher number of circulating CD11b/Gr1 positive cells, extramedullary hematopoiesis and higher plasma levels of G-CSF, IL-1ra, IL-17, IL-6 and CCL2. These data indicate that the local absence of EGFR triggers local and systemic inflammatory responses. Therefore, this model represents a valuable tool to further investigate the control of EGFR in the maintenance of a balanced immuno-homeostasis of the skin.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 18.
