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Melanocytes: from Morphology to Application

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Melanocytes: from Morphology to Application Skin Pharmacol Physiol 2009;22:114–121 Published online: February 4, 2009 DOI: 10.1159/000178870 Melanocytes: From Morphology to Application a a a, b a A. Santiago-Walker L. Li N.K. Haass M. Herlyn a b Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pa. , USA; Immune Imaging Program, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, N.S.W. , Australia Key Words skin is organized into two layers: the dermis, comprised M e l a n o c y t e ؒ K e r a t i n o c y t e ؒ M e l a n o m a ؒ Model ؒ S k i n ؒ of fibroblasts and endothelial cells, provides structure Three-dimensional reconstruct ؒ Drug and strength; and the epidermis, containing basal layer melanocytes, Langerhans cells and stratified layers of ke- ratinocytes which form the protective barrier between Abstract skin and the environment. The epidermis and dermis are Melanocytes in human skin are intricately regulated by kera- separated by the basement membrane which is formed by tinocytes and the surrounding stroma. The development of protein secretions of fibroblasts and keratinocytes. Each melanoma is thought to arise from disrupted melanocyte ho- melanocyte, through dendritic projections, interacts meostasis. It is now known that microenvironment plays a with approximately 36 keratinocytes in what is termed major role in maintenance of cellular homeostasis and can the epidermal melanin unit [1] . The control of melano- contribute to tumor initiation and tumor progression. Histor- cyte homeostasis and the process of melanoma develop- ically, melanocyte studies have been performed in two-di- ment are areas of active research. Here we highlight the mensional culture systems, and often with melanocytes cul- importance of using three-dimensional/organotypic cul- tured in the absence of keratinocytes. Here we present the tures in these studies. biological basis for the use of organotypic, three-dimension- al model systems in the study of melanoma, and highlight the features of the most utilized organotypic model sytems. Melanocyte Homeostasis and Regulation by Copyright © 2009 S. Karger AG, Basel Keratinocytes The proliferating cells of the skin are found primarily Introduction at the basal layer of the epidermis, where the melanocyte to keratinocyte ratio is approximately 1: 5. During child- Melanocytes are specialized, pigment-producing cells hood, melanocytes proliferate as needed during growth derived from the neural crest. Melanocytes respond to to maintain proper skin architecture. In adults, however, ultraviolet (UV) radiation by synthesizing melanin which melanocytes are for the most part quiescent and rarely forms a photoprotective cap over the nucleus of keratino- proliferate, though they maintain the capacity to do so. cytes, protecting skin cells from DNA damage. Human Melanocyte proliferation is primarily under the control © 2009 S. Karger AG, Basel Meenhard Herlyn, MD 1660–5527/09/0222–0114$26.00/0 The Wistar Institute Fax +41 61 306 12 34 3601 Spruce Street, Room 489 E-Mail [email protected] Accessible online at: Philadelphia, PA 19104 (USA) www.karger.com www.karger.com/spp Tel. +1 215 898 3950, Fax +1 215 898 0980, E-Mail [email protected] Keratinocyte-derived DecouplingDivision Migration Recoupling factors SCF, ET-1, GM-CSF E-cadherin Proliferation ACTH, ␣-MSH Melanogenesis Melanogenesis Color version available online E-cadherin SCF CCN3 E-cadherin Desmoglein 1 bFGF DDR1 ET-1 ET-3 HGF CCN3 Fig. 1. Dynamics of melanocyte proliferation in human skin. De- Melanocyte coupling: secretion of endothelin-1 (ET-1) by keratinocytes and DDR1 hepatocyte growth factor/scatter factor (HGF) by fibroblasts re- Integrin sults in the downregulation of E-cadherin expression. Division: bFGF, SCF, HGF Basement Collagen proliferation is induced by secreted factors including stem cell Laminin factor (SCF) secreted by keratinocytes and fibroblasts, basic fibro- membrane blast growth factor (bFGF) by keratinocytes and ET-3 by fibro- blasts. Migration: expression of the matricellular protein CCN3 Fibroblast-derived and its receptor discoidin domain receptor 1 (DDR1) is required factors for proper melanocyte localization on the basement membrane. Recoupling: expression of E-cadherin is increased, recoupling to keratinocytes and dendrite extension occurs. Fig. 2. Melanocyte microenvironment. Keratinocytes secrete fac- tors that promote melanocyte proliferation and melanogenesis including stem cell factor (SCF), endothelin-1 (ET-1), granulo- cyte-macrophage colony-stimulating factor (GM-CSF), adreno- corticotrophic hormone (ACTH) and ␣ -melanocyte stimulating ␣ of keratinocytes. Cell-cell contacts with keratinocytes are hormone ( -MSH). Fibroblasts also contribute to melanocyte regulation by secretion of basic fibroblast growth factor (bFGF), known to be important for the maintenance of melano- SCF and hepatocyte growth factor (HGF). Melanocytes maintain cyte homeostasis. In order for a melanocyte to proliferate, proper localization by binding to collagen and laminin on the the following steps are proposed ( fig. 1 ): (1) retraction of basement membrane. Fukunaga-Kalabis et al. [9, 10] recently re- dendrites and decoupling of melanocytes from surround- ported a role for CCN3 and discoidin domain receptor 1 (DDR1) ing keratinocytes and the basement membrane; (2) pro- in melanocyte basement membrane localization. liferation; (3) repositioning via migration along the base- ment membrane; (4) dendrite extension and recoupling to keratinocytes [2] . Keratinocytes signal to melanocytes to control proliferation via cell-cell contacts mediated by undergo an E- to N-cadherin class switch, allowing me- cadherins as well as by the secretion of signaling mole- lanocytes to escape keratinocyte control as well as pro- cules and growth factors ( fig. 2 ). moting binding to dermal fibroblasts and endothelial The cadherins are a family of cell surface glycopro- cells. Not only are melanoma cells free of keratinocyte teins which mediate calcium-dependent cell adhesion, control over proliferation under these conditions, but in- and represent the transmembrane components of cell- teractions with fibroblasts and endothelial cells allow cell adhesion junctions. They are homophilic binding melanoma cells to invade and survive in the dermis [5] . proteins allowing cells of the same type, or same cad- N-cadherin induces melanoma cell migration, and pro- herin expression pattern, to bind and organize into tis- motes survival via activation of Akt, increased ␤ -catenin sues [3] . In skin, cadherin expression is cell type specific expression and inactivation of the proapoptotic protein and critical for maintenance of skin architecture and reg- Bad [6] . The importance of this cadherin class switch is ulation of homeostasis. E-cadherin is expressed on mela- supported by experiments showing that re-expression of nocytes, keratinocytes and Langerhans cells of the epi- E-cadherin in human melanoma cells restored keratino- dermis, while N-cadherin is expressed on dermal fibro- cyte coupling and inhibited invasive potential [7] . blasts and endothelial cells [4] . This differential cadherin Integrin-mediated attachment also plays a role in me- expression is exploited in melanoma, where melanocytes lanocyte maintenance. Integrins are cell surface recep- Melanocytes: From Morphology to Skin Pharmacol Physiol 2009;22:114–121 115 Application tors for extracellular matrix (ECM) proteins such as lam- hesion molecule (Mel-CAM/MUC18) and ␤ 3 integrin inin and collagen. Integrins, which are comprised of het- [13] . Melanocyte phenotype can be rescued by the addi- erodimers of ␣ - and ␤ -subunits, connect the ECM to the tion of keratinocytes to melanocyte cultures. Keratino- actin cytoskeleton and are required for melanocyte at- cytes regain control over melanocyte proliferation such tachment to and release from the basement membrane that when keratinocytes and melanocytes are seeded at during migration. In addition to their role in attachment, fixed ratios, these ratios are maintained as the cells pro- integrins impact multiple aspects of cell physiology in- liferate. The multidendritic morphology of melanocytes cluding proliferation, differentiation and survival. Al- is restored upon coculture. Most interestingly, expression tered integrin expression is thought to help melanocytes of melanoma-associated antigens is lost within 3–4 days survive in the dermis, specifically integrins ␣v ␤3 and of coculture [14] . In support of this, in vivo nevocytes ␣5 ␤1 are indicative of melanoma progression [8] . (nests or groupings of melanocytes) residing in the der- Recently, work from our laboratory has revealed a role mis, separated from keratinocytes, express melanoma- for the matricellular protein CCN3 in melanocyte ho- associated antigens while nevocytes localized in the epi- meostasis. CCN3 (nephroblastoma overexpressed) was dermis do not. Coculture of dermal nevocytes with kera- found to be upregulated in melanocytes and secreted in tinocytes can restore normal melanocytic phenotype response to coculture with keratinocytes. CCN3 expres- [13] . Further evidence for the role of keratinocytes on me- sion inhibited melanocyte proliferation and was required lanocyte homeostatis comes from a recently developed for proper melanocyte localization on the basement mouse model in which the retinoid X receptor ␣ (RXR ␣ ) membrane. CCN3, via the receptor tyrosine kinase dis- was knocked out selectively in keratinocytes. Keratino- coidin domain receptor 1 (DDR1), promotes
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