Immunohistochemical Evaluation and Clinicopathological Correlation of Mer and Axl Tyrosine Kinase TAM Receptors in Cutaneous Melanoma
Keywords:
malignant melanoma, tyrosine kinase, Mer, Axl, receptors, therapy, TAMAbstract
Background: Malignant melanoma (MM) is potentially the most dangerous form of skin tumor. In the last few years, the so-called TAM receptors, a unique family of tyrosine kinase (TK) receptors, have become increasingly important.
Objectives: To evaluate Mer and Axl TAM receptor expression to find clinicopathological features that could explain the biological behavior of MM.
Patients and Methods: Clinicopathological data were obtained from an MM electronic database at our Institute. We reviewed 24 cutaneous MM specimens. TAM receptor expression was assayed using immunohistochemistry. Combinative semiquantitative scoring was used for the evaluation of TAM receptor expression (MerTK and AxlTK). Appropriate statistical methods were used to evaluate a possible correlation between TAM receptor expression and the clinicopathological variables of the MM samples (univariate analysis and multivariate analysis).
Results: MerTK and AxlTK were expressed differently in the MM samples, with a major expression of the first receptor. The cells of the tumor microenvironment contributed to the majority of the total score. A significant association was found between AxlScore and the site of the tumor and between AxlScore and the variable ulceration; another correlation was found between MerScore and the following characteristics: pathological stage of the tumor (pT), sex, ulceration, and tumor-infiltrating lymphocytes.
Conclusions: All correlations between the expression of MerTK and AxlTK with the clinical and histological variables of MM should be validated in a large group of people in order to increase the validity and the impact of our observations, with subsequently therapeutic implications in the era of the “targeted therapy.”
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34.
Paolino G, Panetta C, Cota C, et al. Vitamin D receptor immunohistochemistry variability in sun-exposed and non-sun-exposed melanomas. Melanoma Res. 2017;27(1):17-23.
Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483-6488.
Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell. 2012;150(2):251-263.
Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516.
Prasad D, Rothlin CV, Burrola P, et al. TAM receptor function in the retinal pigment epithelium. Mol Cell Neurosci. 2006;33(1):96-108.
Schlegel J, Sambade MJ, Sather S, et al. MERTK receptor tyrosine kinase is a therapeutic target in melanoma. J Clin Invest. 2013;123(5):2257-2267.
Zhu S, Wurdak H, Wang Y, et al. A genomic screen identifies TYRO3 as a MITF regulator in melanoma. Proc Natl Acad Sci U S A. 2009;106(40):17025-17030.
Tworkoski KA, Platt JT, Bacchiocchi A, Bosenberg M, Boggon TJ, Stern DF. MERTK controls melanoma cell migration and survival and differentially regulates cell behavior relative to AXL. Pigment Cell Melanoma Res. 2013;26(4):527-541.
Fedchenko N, Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue—a review. Diagn Pathol. 2014;9:221.
Sensi M, Catani M, Castellano G, et al. Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. J Invest Dermatol. 2011;131(12):2448-2457.
Salmi S, Siiskonen H, Sironen R, et al. The number and localization of CD68+ and CD163+ macrophages in different stages of cutaneous melanoma. Melanoma Res. 2019;29(3):237-247.
Walker MJ, Ronan SG, Han MC, Beattie CW, Das Gupta TK. Interrelationship between histopathologic characteristics of melanoma and estrogen receptor status. Cancer. 1991;68(1):184-188.
de Giorgi V, Mavilia C, Massi D, et al. Estrogen receptor expression in cutaneous melanoma: a real-time reverse transcriptase-polymerase chain reaction and immunohistochemical study. Arch Dermatol. 2009;145(1):30-36.
Holland SJ, Pan A, Franci C, et al. R428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res. 2010;70(4):1544-1554.
Wu Y, Singh S, Georgescu MM, Birge RB. A role for Mer tyrosine kinase in alphavbeta5 integrin-mediated phagocytosis of apoptotic cells. J Cell Sci. 2005;118(Pt 3):539-553.
Haanen JB, Baars A, Gomez R, et al. Melanoma-specific tumor-infiltrating lymphocytes but not circulating melanoma-specific T cells may predict survival in resected advanced-stage melanoma patients. Cancer Immunol Immunother. 2006;55(4):451-458.
Monn KR, Choi YD, Kim JM, et al. Genetic alterations in primary acral melanoma and acral melanocytic nevus in Korea: common mutated genes show distinct cytomorphological features. J Invest Dermatol. 2018;138(4):933-945.
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