Molecular and cellular pathogenesis of melanoma initiation and progression
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Cellular and Molecular Life Sciences
Review
Molecular and cellular pathogenesis of melanoma initiation and progression Tarik Regad
Received: 31 October 2012 / Revised: 7 March 2013 / Accepted: 11 March 2013 © Springer Basel 2013
Abstract Melanoma is a malignant tumor of melanocytes that can spread to other organs of the body, resulting in severe and/or lethal malignancies. Melanocytes are pigment-producing cells found in the deep layer of the epidermis and are originated from melanocytes stem cells through a cellular process called melanogenesis. Several genes and epigenetic and micro-environmental factors are involved in this process via the regulation and maintenance of the balance between melanocytes stem cells proliferation and their differentiation into melanocytes. Dysregulation of this balance through gain or loss of function of key genes implicated in the control and regulation of cell cycle progression and/or differentiation results in melanoma initiation and progression. This review aims to provide a comprehensive overview about the origin of melanocytes, the oncogenic events involved in melanocytes stem cells transformation, and the mechanisms implicated in the perpetuation of melanoma malignant phenotype. Keywords Cancer stem cells · Malignant melanoma-initiating cells · HAGE · ABCB5 · MicroRNA · Chemoresistance · Melanocyte · RAS signaling
Introduction Melanocytes begin their journey at the gastrula stage of development where the neural crest generates glialmelanocyte progenitors that commit to the production of
T. Regad (*) The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham NG11 8NS, UK e-mail: [email protected]
melanoblasts [1, 2]. These cells later generate melanocyte stem cells (MSCs), found in the hair follicle where they ensure the continuous generation of melanocytes, the cells responsible for melanin-pigment production throughout the adult life. These cells possess stem cell-like properties associated with self-renewal and differentiation. The process of transformation of MSCs results in the initiation of melanoma and/or its progression. In this regard, several factors involved in the early development and survival of MSCs such as MITF or EDNRB are overexpressed in melanoma and act as “survival” oncogenes [3–5]. Other causes of MSC transformation involve genetic mutations targeting key genes implicated in cell cycle regulation, cell differentiation, and signal transduction. Examples include mutations in tumor suppressor genes such CDKN2A and CDK4 and gain-of-function mutations affecting the RAS-RAF-MAPK pathways responsible for nearly 75 % (BRAF and NRAS mutations) of melanoma cases [6, 7]. The implication of epigenetic factors in melanoma progression is reflected by the hypomethylation or hypermethylation events affecting the expression of oncogenes and tumor suppressors, respectively. Up-regulation or down-regulation of microRNAs expression, which act as tumor suppressors or oncogenes through the re
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