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Pigment Cell & Melanoma Research Jan 2021The second messenger cyclic adenosine monophosphate (cAMP) regulates numerous functions in both benign melanocytes and melanoma cells. cAMP is generated from two... (Review)
Review
The second messenger cyclic adenosine monophosphate (cAMP) regulates numerous functions in both benign melanocytes and melanoma cells. cAMP is generated from two distinct sources, transmembrane and soluble adenylyl cyclases (tmAC and sAC, respectively), and is degraded by a family of proteins called phosphodiesterases (PDEs). cAMP signaling can be regulated in many different ways and can lead to varied effects in melanocytes. It was recently revealed that distinct cAMP signaling pathways regulate pigmentation by either altering pigment gene expression or the pH of melanosomes. In the context of melanoma, many studies report seemingly contradictory roles for cAMP in tumorigenesis. For example, cAMP signaling has been implicated in both cancer promotion and suppression, as well as both therapy resistance and sensitization. This conundrum in the field may be explained by the fact that cAMP signals in discrete microdomains and each microdomain can mediate differential cellular functions. Here, we review the role of cAMP signaling microdomains in benign melanocyte biology, focusing on pigmentation, and in melanomagenesis.
Topics: Adenylyl Cyclases; Animals; Cyclic AMP; Gene Expression Regulation; Humans; Melanocytes; Melanoma; Pigmentation; Pigmentation Disorders
PubMed: 32777162
DOI: 10.1111/pcmr.12920 -
Pigment Cell & Melanoma Research Jul 2024Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi,... (Review)
Review
Melanin synthesis involves the successful coordination of metabolic pathways across multiple intracellular compartments including the melanosome, mitochondria, ER/Golgi, and cytoplasm. While pigment production offers a communal protection from UV damage, the process also requires anabolic and redox demands that must be carefully managed by melanocytes. In this report we provide an updated review on melanin metabolism, including recent data leveraging new techniques, and technologies in the field of metabolism. We also discuss the many aspects of melanin synthesis that intersect with metabolic pathways known to impact melanoma phenotypes and behavior. By reviewing the metabolism of melanin synthesis, we hope to highlight outstanding questions and opportunities for future research that could improve patient outcomes in pigmentary and oncologic disease settings.
Topics: Melanins; Melanocytes; Humans; Melanoma; Animals
PubMed: 38445351
DOI: 10.1111/pcmr.13165 -
Pigment Cell & Melanoma Research Jul 2021
Topics: Humans; Melanocytes; Pigmentation Disorders; Skin Neoplasms; Skin Pigmentation
PubMed: 34255940
DOI: 10.1111/pcmr.12997 -
Actas Dermo-sifiliograficas Apr 2022The study of subungual melanocytic lesions can present challenges because of the clinical and histologic characteristics of the nail unit and the difficulty of...
The study of subungual melanocytic lesions can present challenges because of the clinical and histologic characteristics of the nail unit and the difficulty of performing nail biopsies and processing specimens. These lesions can be even more challenging in children due to differences in clinical and epidemiological profiles between the adult and pediatric populations. Many of the clinical features of subungual melanocytic lesions that would raise alarm in an adult do not have the same implications in children. Consensus is also lacking on when a nail biopsy is needed to rule out malignancy in the pediatric setting. In view of these considerations and the rarity of subungual melanoma in childhood, the recommended approach in most cases is a watch-and-wait strategy. Subungual melanocytic lesions in children may also show atypical histopathologic features that are not necessarily associated with aggressive behavior. Subungual melanoma is very rare in childhood, with just 21 cases described to date. None of the patients developed visceral metastasis or died as a result and the diagnosis was controversial in many of the cases. Considering the above and the significantly higher frequency and particular characteristics of longitudinal melanonychia with a benign etiology in children, subungual melanocytic lesions should be managed differently in this setting than in adults. In most cases, a watch-and-wait approach is the most appropriate strategy.
Topics: Adult; Biopsy; Child; Humans; Melanocytes; Melanoma; Nail Diseases; Nails
PubMed: 35623729
DOI: 10.1016/j.ad.2021.10.007 -
Annals of Anatomy = Anatomischer... Nov 2021The human choroid derives from the mesectoderm, except the melanocytes originating from the neuroectoderm. To date, it is unclear whether all choroidal melanocytes share...
BACKGROUND
The human choroid derives from the mesectoderm, except the melanocytes originating from the neuroectoderm. To date, it is unclear whether all choroidal melanocytes share the same origin or might have different origins. The purpose of this study was to screen immunohistochemically for mesenchymal elements in the adult healthy human choroid, in the malignant melanoma of the choroid, as well as in the developing human fetal choroid.
METHODS
Human choroids were obtained from cornea donors and prepared as flat whole mounts for paraffin- and cryoembedding. Globes enucleated for choroidal melanoma and eyes from human fetuses between 11 and 20 weeks of gestation were also embedded in paraffin. Sections were processed for immunohistochemistry of the mesenchymal marker vimentin, the melanocyte marker Melan-A, and the macrophage marker CD68, followed by light-, fluorescence-, and confocal laser scanning-microscopy.
RESULTS
The normal choroid contained 499 ± 139 vimentin, 384 ± 78 Melan-A, and 129 ± 57 CD68 immunoreactive cells/mm. The vimentin immunopositive cell density was significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). By confocal microscopy, 24 ± 8% of all choroidal melanocytes displayed vimentin immunoreactivity. In choroidal melanomas, numerous melanoma cells of the epithelioid and spindle cell type revealed immunopositivity for both vimentin and Melan-A. The intratumoral density of vimentin immunoreactive cells was 1758 ± 106 cells/mm, significantly higher than the density of Melan-A and CD68 immunopositive cells (p < 0.001, respectively). Comparing to healthy choroidal tissue, the choroidal melanomas revealed significantly higher densities of vimentin, Melan-A, and CD68 immunoreactive cells (p < 0.001, respectively). In the developing human fetal choroid, numerous vimentin and Melan-A immunopositive cells were detected not before the 16th week of gestation, with some of them showing colocalization of vimentin and Melan-A.
CONCLUSIONS
The adult healthy human choroid is endowed with a significant number of vimentin immunopositive mesenchymal structures, including a subpopulation of vimentin immunoreactive choroidal melanocytes. These vimentin immunopositive melanocytic cells are also present in choroidal melanomas as well as in the developing human fetal choroid. Therefore, different embryologic origins can be considered for choroidal melanocytes.
Topics: Choroid; Humans; Melanocytes; Melanoma; Skin Neoplasms; Uveal Neoplasms
PubMed: 34082079
DOI: 10.1016/j.aanat.2021.151775 -
Gerontology 2021Although microphthalmia-associated transcription factor (MITF) has been known for decades as a key regulator for melanocytic differentiation, recent studies expanded its... (Review)
Review
Although microphthalmia-associated transcription factor (MITF) has been known for decades as a key regulator for melanocytic differentiation, recent studies expanded its other roles in multiple biological processes. Among these newfound roles, the relationship between MITF and aging is attractive; however, the underlying mechanism remains elusive. Here, we review the documented cues that highlight the implication of MITF in the aging process and particularly discuss the possible mechanisms underlying the participation of MITF in cellular senescence. First, it summarizes the association of MITF with melanocytic senescence, including the roles of MITF in cell cycle regulation, DNA damage repair, oxidative stress response, and the generation of senescence-associated secretory phenotype. Then, it collects the information involving MITF-related senescent changes in nonmelanocytes, such as retinal pigment epithelium cells, osteoclasts, and cardiomyocytes. This review may deepen the understanding of MITF function and be helpful to develop new strategies for improving geriatric health.
Topics: Aging; Cell Differentiation; Cellular Senescence; Humans; Melanocytes; Microphthalmia-Associated Transcription Factor
PubMed: 33940580
DOI: 10.1159/000515525 -
Pigment Cell & Melanoma Research Mar 2021
Topics: Biomedical Research; Humans; Japan; Melanocytes; Melanoma
PubMed: 33682372
DOI: 10.1111/pcmr.12928 -
Pigment Cell & Melanoma Research Sep 2023Melanoma, a lethal malignancy that arises from melanocytes, exhibits a multiplicity of clinico-pathologically distinct subtypes in sun-exposed and non-sun-exposed areas.... (Review)
Review
Melanoma, a lethal malignancy that arises from melanocytes, exhibits a multiplicity of clinico-pathologically distinct subtypes in sun-exposed and non-sun-exposed areas. Melanocytes are derived from multipotent neural crest cells and are present in diverse anatomical locations, including skin, eyes, and various mucosal membranes. Tissue-resident melanocyte stem cells and melanocyte precursors contribute to melanocyte renewal. Elegant studies using mouse genetic models have shown that melanoma can arise from either melanocyte stem cells or differentiated pigment-producing melanocytes depending on a combination of tissue and anatomical site of origin and activation of oncogenic mutations (or overexpression) and/or the repression in expression or inactivating mutations in tumor suppressors. This variation raises the possibility that different subtypes of human melanomas (even subsets within each subtype) may also be a manifestation of malignancies of distinct cells of origin. Melanoma is known to exhibit phenotypic plasticity and trans-differentiation (defined as a tendency to differentiate into cell lineages other than the original lineage from which the tumor arose) along vascular and neural lineages. Additionally, stem cell-like properties such as pseudo-epithelial-to-mesenchymal (EMT-like) transition and expression of stem cell-related genes have also been associated with the development of melanoma drug resistance. Recent studies that employed reprogramming melanoma cells to induced pluripotent stem cells have uncovered potential relationships between melanoma plasticity, trans-differentiation, and drug resistance and implications for cell or origin of human cutaneous melanoma. This review provides a comprehensive summary of the current state of knowledge on melanoma cell of origin and the relationship between tumor cell plasticity and drug resistance.
Topics: Animals; Mice; Humans; Melanoma; Skin Neoplasms; Cell Plasticity; Melanocytes; Cell Differentiation; Drug Resistance; Induced Pluripotent Stem Cells; Neural Crest
PubMed: 37132530
DOI: 10.1111/pcmr.13092 -
Pigment Cell & Melanoma Research Mar 2021Melanoma arises from the melanocyte lineage and is the most aggressive and lethal form of skin cancer. There are several genetic, genomic, and cellular changes... (Review)
Review
Melanoma arises from the melanocyte lineage and is the most aggressive and lethal form of skin cancer. There are several genetic, genomic, and cellular changes associated with melanoma initiation. Here, we discuss these alterations and the melanoma cells of origin in which they are proposed to promote melanomagenesis.
Topics: Animals; Carcinogenesis; Gene Expression Regulation, Neoplastic; Humans; Melanocytes; Melanoma; Skin Neoplasms
PubMed: 33283422
DOI: 10.1111/pcmr.12950 -
International Journal of Molecular... Dec 2020The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into... (Review)
Review
The epidermis is located in the outermost layer of the living body and is the place where external stimuli such as ultraviolet rays and microorganisms first come into contact. Melanocytes and melanin play a wide range of roles such as adsorption of metals, thermoregulation, and protection from foreign enemies by camouflage. Pigmentary disorders are observed in diseases associated with immunodeficiency such as Griscelli syndrome, indicating molecular sharing between immune systems and the machineries of pigment formation. Melanocytes express functional toll-like receptors (TLRs), and innate immune stimulation via TLRs affects melanin synthesis and melanosome transport to modulate skin pigmentation. TLR2 enhances melanogenetic gene expression to augment melanogenesis. In contrast, TLR3 increases melanosome transport to transfer to keratinocytes through Rab27A, the responsible molecule of Griscelli syndrome. TLR4 and TLR9 enhance tyrosinase expression and melanogenesis through p38 MAPK (mitogen-activated protein kinase) and NFκB signaling pathway, respectively. TLR7 suppresses microphthalmia-associated transcription factor (MITF), and MITF reduction leads to melanocyte apoptosis. Accumulating knowledge of the TLRs function of melanocytes has enlightened the link between melanogenesis and innate immune system.
Topics: Animals; Humans; Immunity, Innate; Melanins; Melanocytes; Melanosomes; Skin Pigmentation; Toll-Like Receptors
PubMed: 33371432
DOI: 10.3390/ijms21249769