The disintegrin-metalloproteinases ADAM10 and ADAM17 are upregulated in cutaneous squamous cell carcinomas

Sir, Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant neoplasm of the human skin. The incidence of CSCC is increasing, representing a major medical and economic problem. CSCC is characterized by a marked propensity for invasion and metastatic capacity. The degree of cellular differentiation, tumor thickness, location, and other features have prognostic value. Identification of the pathogenic mechanisms for CSCC could facilitate the treatment and prevention of this cancer. There is increasing evidence that the ADAMs (a disintegrin andmetalloprotease) are differentially expressed in malignant tumors and may, therefore, participate in the pathogenesis of carcinomas. Among proteases, 2 ADAMs (ADAM10 and ADAM17) have been of special interest, due to their characteristics of releasing and activating several ligands for the epidermal growth factor receptor (EGFR)/human EGFR (HER) family of receptors. HB-EGF, important substrate of ADAM10 and 17, plays a key role in the transactivation of the EGFR by G protein-coupled receptors. Recent studies have indicated that HB-EGF gene expression is significantly elevated in variety of human cancers and its expression level is much higher than those of the other EGFR ligands. Interestingly, it was postulated that HB-EGF might promote tumor growth of CSCC. In this study, we investigated for the first time the expression and localization of ADAM10 and 17 in different histologic subtypes of CSCC, using immunohistochemical analysis. The study was approved by the ethical committee of the Catholic University of Korea (DC12TIG10010). Formalin-fixed, paraffin-embedded specimens were used. CSCC can be divided into 3 histological subtypes, according to differentiation. The following histological specimens were examined: CSCC (n D 26) [histological subtypes: well differentiated (nD12); differentiated cells are greater than 75%, moderately differentiated (n D 7); differentiated cells are 25–75%, poorly differentiated (n D 7); differentiated cells are less than 25%]. Immunohistochemical analysis was performed using specific polyclonal antibodies and a streptavidin-peroxidase technique with Dako Kit (DAKO REAL detection system alkaline phosphatase/ RED rabbit/mouse, Dako, Cat.No. K5005). The primary antibody to the C-terminus of ADAM10 was from Santa Cruz (Heidelberg, Germany), the ADAM17 antibody from eBioscience (Malden, Netherland). The antibodies were used in the following dilutions: ADAM10 (1:50), and ADAM17 (1:100). Microscopic analysis was performed by 2 independent observers (S. O. and J. R.). The degree of expression was graded semi-quantitatively as follows: ¡, negative (0%); C, focal (1–20%); CC, moderate (21–50%); and CCC, diffuse (>50 %). The ADAM 10, 17 immunoreactivity was also assessed with respect to localization (membranous, cytoplasmic and nuclear). Mann-Whitney test was performed to compare ADM10 and ADAM17 expression between normal and CSCC epidermis, respectively. Kruskal-Wallis test was done to determine the overall difference among groups in terms of ADAM10 and ADAM17, respectively. Post hoc Mann-Whitney test was subsequently performed