Melanoma
Mental Health and Illness
Circumstances forcing individuals and families to flee set the stage for disruptions in mental health and forge resilience. Individual characteristics and conditions premigration, perimigration, and postmigration influence health, mental health, care-seeking behavior, and stages of well-being and successful resettlement. Primary care providers have strategies to promote mental well-being, including focusing on resilience and social determinants of health. Integrated or collaborative care models are ideal for delivering optimum care for refugee and immigrant communities. Connecting primary and behavioral care promotes a team approach; provides comprehensive, whole-person care; and relies on participation of patients and families.Automated Dermatological Diagnosis: Hype or Reality?
In this issue of the Journal of Investigative Dermatology, Han et al. (2018) have made a landmark contribution to the application of artificial intelligence (AI) in dermatologic diagnosis. Although previous studies have reported that computer algorithms can successfully diagnose skin cancer from medical images with human equivalency (Esteva et al., 2017; Ferris et al., 2015; Marchetti et al., 2018; Menzies et al., 2005), Han et al. have made their computer algorithm publicly available for external testing.Melatonin: A Cutaneous Perspective on its Production, Metabolism, and Functions
Melatonin, an evolutionarily ancient derivative of serotonin with hormonal properties, is the main neuroendocrine secretory product of the pineal gland. Although melatonin is best known to regulate circadian rhythmicity and lower vertebrate skin pigmentation, the full spectrum of functional activities of this free radical-scavenging molecule, which also induces/promotes complex antioxidative and DNA repair systems, includes immunomodulatory, thermoregulatory, and antitumor properties. Because this plethora of functional melatonin properties still awaits to be fully appreciated by dermatologists, the current review synthesizes the main features that render melatonin a promising candidate for the management of several dermatoses associated with substantial oxidative damage.Replenishing Regulatory T Cells to Halt Depigmentation in Vitiligo
Vitiligo is a cutaneous autoimmune disease, especially devastating to patients with darker skin tones because of the contrast between unaffected and lesional skin. We studied immune cells infiltrating vitiligo skin and found very few regulatory T cells (Tregs). Vitiligo was not associated with a reduced frequency or function of circulating Tregs. To manipulate Treg function, we used mouse models expressing melanocyte-reactive TCRs, following changes in pelage color. We also isolated splenocytes to measure Treg function and evaluated cutaneous Treg abundance.Extracellular Vesicles as Biomarkers and Therapeutics in Dermatology: A Focus on Exosomes
Extracellular vesicles (exosomes, microvesicles, and apoptotic bodies) are ubiquitous in human tissues, circulation, and body fluids. Of these vesicles, exosomes are of growing interest among investigators across multiple fields, including dermatology. The characteristics of exosomes, their associated cargo (nucleic acids, proteins, and lipids), and downstream functions are vastly different, depending on the cell origin. Here, we review concepts in extracellular vesicle biology, with a focus on exosomes, highlighting recent studies in the field of dermatology.Association between Body Mass Index, C-Reactive Protein Levels, and Melanoma Patient Outcomes
Obesity is a known risk factor for cancer development (Arnold et al., 2016; Basen-Engquist and Chang, 2011; Renehan et al., 2015) and death (Calle et al., 2003). Obesity has been associated with an increased risk of developing melanoma in men (Sergentanis et al., 2013) and with thicker primary melanomas (Skowron et al., 2015). The inflammatory adipokine leptin promotes melanoma progression in mice (Amjadi et al., 2011; Brandon et al., 2009; Gogas et al., 2008); elevated leptin levels may predict melanoma sentinel node metastasis (Oba et al., 2016).Noninvasive Determination of Melanoma Depth using a Handheld Photoacoustic Probe
When a clinically suspicious pigmented lesion is biopsied and histologic examination shows melanoma, tumor depth, or Breslow’s depth (BD), is the key parameter that both determines surgical margins for definitive excision and serves as an indication to perform sentinel lymph node biopsy (Smith and MacNeil, 2011). Optimally, BD is measured during an initial excisional biopsy that includes the entire lesion. However, in many cases an incisional biopsy is performed that takes a sample of only a portion of the tumor, possibly resulting in an inaccurate measurement (Guitera and Menzies, 2011; Sellheyer et al., 2010).CXCR3 Depleting Antibodies Prevent and Reverse Vitiligo in Mice
Vitiligo is a disfiguring skin disease in which melanocytes with intrinsic abnormalities are targeted and destroyed by autoreactive CD8+ T cells in the epidermis, resulting in patchy depigmentation (Palermo et al., 2001; van den Boorn et al., 2009, and reviewed in Richmond et al., 2013). Although it is one of the most common autoimmune diseases, affecting 1% of the population worldwide, there are no Food and Drug Administration-approved treatments. Previous work from our lab has shown that CD8+ T-cell recruitment to the skin in a mouse model of vitiligo is dependent on IFNγ (Harris et al., 2012) and the downstream CXCR3 chemokine system (Rashighi et al., 2014).Preclinical Advances with Multiphoton Microscopy in Live Imaging of Skin Cancers
Conventional, static analyses have historically been the bedrock and tool of choice for the study of skin cancers. Over the past several years, in vivo imaging of tumors using multiphoton microscopy has emerged as a powerful preclinical tool for revealing detailed cellular behaviors from the earliest moments of tumor development to the final steps of metastasis. Multiphoton microscopy allows for deep tissue penetration with relatively minor phototoxicity, rendering it an effective tool for the long-term observation of tumor evolution.Cancer Stem Cells in Squamous Cell Carcinoma
Cancer stem cells (CSCs) are found in many cancer types, including squamous cell carcinoma (SCC). CSCs initiate cancer formation and are linked to metastasis and resistance to therapies. Studies have revealed that several distinct CSC populations coexist in SCC and that tumor initiation and metastatic potential of these populations can be uncoupled. Therefore, it is critical to understand CSC biology to develop novel CSC-targeted therapies for patients with SCC with poor prognoses. This review compares the properties of CSCs in SCC with normal stem cells in the skin, summarizes current advances and characteristics of CSCs, and considers the challenges for CSC-targeted treatment of SCC.The Senescence-Associated Secretory Phenotype: Critical Effector in Skin Cancer and Aging
Cellular senescence, a state of stable cell cycle arrest in response to cellular stress, is an indispensable mechanism to counter tumorigenesis by halting the proliferation of damaged cells. However, through the secretion of an array of diverse cytokines, chemokines, growth factors, and proteases known as the senescence-associated secretory phenotype (SASP), senescent cells can paradoxically promote carcinogenesis. Consistent with this, removal of senescent cells delays the onset of cancer and prolongs lifespan in vivo, potentially in part through SASP reduction.Consensus of Melanoma Gene Expression Subtypes Converges on Biological Entities
Identification of recurrent mutation in the BRAF oncogene in melanoma has led to the development of highly selective kinase inhibitors (Larkin et al., 2014). Although dramatic treatment responses are initially observed, responses are rarely durable. The mutational classification based on BRAF, NRAS, and NF1 mutations that has been established, however, is nonoverlapping with classification derived from gene expression profiling (The Cancer Genome Atlas Network [TCGA], 2015; Jönsson et al., 2010).RASopathy Gene Mutations in Melanoma
Next-generation sequencing of melanomas has unraveled critical driver genes and genomic abnormalities, mostly defined as occurring at high frequency. In addition, less abundant mutations are present that link melanoma to a set of disorders, commonly called RASopathies. These disorders, which include neurofibromatosis and Noonan and Legius syndromes, harbor germline mutations in various RAS/mitogen-activated protein kinase signaling pathway genes. We highlight shared amino acid substitutions between this set of RASopathy mutations and those observed in large-scale melanoma sequencing data, uncovering a significant overlap.The Role of Neutrophilic Inflammation, Angiotropism, and Pericytic Mimicry in Melanoma Progression and Metastasis
Angiotropism in melanoma correlates with ulceration and poor prognosis. It has been shown to be a marker of pericytic mimicry, that is, the spreading of tumor cells in a pericyte location along abluminal vascular surfaces. Such extravascular tumor spread may represent another form of tumor plasticity with reversion to a neural crest cell migratory phenotype. In a murine melanoma model, it has recently been demonstrated that neutrophilic skin inflammation promotes angiotropism and metastatic spread of primary melanomas.Telomerase Expression by Aberrant Methylation of the TERT Promoter in Melanoma Arising in Giant Congenital Nevi
Telomeres are tandem repeats of the noncoding DNA structures at the end of human chromosomes that protect the coding DNA and the integrity of the genome (Blackburn, 1991). The ability to sustain telomere length confers unlimited proliferative capacity to cancer cells. In most cancers telomere length is maintained by the activity of the enzyme telomerase (Kim et al., 1994), whose catalytic subunit is encoded by the telomerase reverse transcriptase (TERT) gene. However, until recently, the underlying mechanisms for telomerase activation in cancer cells were largely unknown.Validity of Self-Reported Psoriasis in a General Population: The HUNT Study, Norway
A high prevalence of psoriasis has been reported in Norway, ranging from 4.8% to 11.8% (Bo et al., 2008; Danielsen et al., 2013; Kavli et al., 1985; Parisi et al., 2013). Prevalence estimates depend crucially on the validity of questionnaires (Jagou et al., 2006; Kurd and Gelfand, 2009; Lima et al., 2013; Plunkett et al., 1999; Rea et al., 1976; Wolkenstein et al., 2009). We aimed to validate self-reported psoriasis in a large population-based study in Norway using clinical skin examination performed by dermatologists as the gold standard and also to estimate the validation-based prevalence of psoriasis in a general Norwegian population.Melanoma-Directed Activation of Apoptosis Using a Bispecific Antibody Directed at MCSP and TRAIL Receptor-2/Death Receptor-5
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an immune effector protein that induces apoptosis in virus-infected and cancer cells by activating death receptor-4 (DR4) and/or death receptor-5 (DR5) without deleterious activity toward DR4/DR5-expressing normal cells (Ashkenazi et al., 2008). Consequently, DR4/DR5 agonists are promising anticancer agents. Treatment with “first-generation” DR4/DR5-targeted therapeutics, such as recombinant human soluble tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) and agonistic DR4/DR5 antibodies, was well tolerated but had disappointing clinical activity (Ashkenazi, 2015).
