A Multimodal Drug-Diet-Immunotherapy Combination Restrains Melanoma Progression and Metastasis.

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet.

Journey through the spectacular landscape of melanocortin 1 receptor.

The physiological role of α-melanocyte stimulating hormone in regulating integumental pigmentation of many vertebrate species has been recognized since the 1960's. However, its physiological significance for human pigmentation remained enigmatic until the 1990's. α-Melanocyte stimulating hormone and related melanocortins are synthesized locally in the skin, primarily by keratinocytes, in addition to the pituitary gland, and therefore act as paracrine factors for melanocytes.

Distinct cAMP Signaling Microdomains Differentially Regulate Melanosomal pH and Pigmentation.

cAMP signaling is a well-established regulator of melanin synthesis. Two distinct cAMP signaling pathways-the transmembrane adenylyl cyclase pathway, activated primarily by the MC1R, and the soluble adenylyl cyclase (sAC) pathway-affect melanin synthesis. The sAC pathway affects melanin synthesis by regulating melanosomal pH, and the MC1R pathway affects melanin synthesis by regulating gene expression and post-translational modifications.

Differential Induction of Reactive Oxygen Species and Expression of Antioxidant Enzymes in Human Melanocytes Correlate with Melanin Content: Implications on the Response to Solar UV and Melanoma Susceptibility.

Constitutive pigmentation determines the response to sun exposure and the risk for melanoma, an oxidative stress-driven tumor. Using primary cultures of human melanocytes, we compared the effects of constitutive pigmentation on their antioxidant response to solar UV. The quantitation of eumelanin and pheomelanin showed that the eumelanin content and eumelanin to pheomelanin ratio correlated inversely with the basal levels of reactive oxygen species (ROS).

Participation of keratinocyte- and fibroblast-derived factors in melanocyte homeostasis, the response to UV, and pigmentary disorders.

Human epidermal melanocytes play a central role in sensing the environment and protecting the skin from the drastic effects of solar ultraviolet radiation and other environmental toxins or inflammatory agents. Melanocytes survive in the epidermis for decades, which subjects them to chronic environmental insults. Melanocytes have a poor self-renewal capacity; therefore, it is critical to ensure their survival with genomic stability.

Measurement of Melanin Metabolism in Live Cells by [U-C]-L-Tyrosine Fate Tracing Using Liquid Chromatography-Mass Spectrometry.

Melanin synthesis occurs within a specialized organelle called the melanosome. Traditional methods for measuring melanin levels rely on the detection of chemical degradation products of melanin by high-performance liquid chromatography. Although these methods are robust, they are unable to distinguish between melanin synthesis and degradation and are best suited to measure melanin changes over long periods of time.

The enigma and challenges of vitiligo pathophysiology and treatment.

Vitiligo is the most common acquired pigmentary disorder, which afflicts 0.5%-1% of the world population, and is characterized by depigmented skin patches resulting from melanocyte loss. Vitiligo has a complex etiology and varies in its manifestations, progression, and response to treatment.

Light or Dark Pigmentation of Engineered Skin Substitutes Containing Melanocytes Protects Against Ultraviolet Light-Induced DNA Damage In Vivo.

Engineered skin substitutes (ESS) containing autologous fibroblasts and keratinocytes provide stable wound closure in patients with large, full-thickness burns, but are limited by hypopigmentation due to absence of added melanocytes. DNA damage caused by ultraviolet radiation (UV) increases risk for skin cancer development. In human skin, melanocytes provide pigmentation that protects skin from UV-induced DNA damage.

Endothelin-1 and α-melanocortin have redundant effects on global genome repair in UV-irradiated human melanocytes despite distinct signaling pathways.

Human melanocyte homeostasis is sustained by paracrine factors that reduce the genotoxic effects of ultraviolet radiation (UV), the major etiological factor for melanoma. The keratinocyte-derived endothelin-1 (End-1) and α-melanocyte-stimulating hormone (α-MSH) regulate human melanocyte function, proliferation and survival, and enhance repair of UV-induced DNA photoproducts by binding to the G - and G -protein-coupled endothelin B receptor (EDNRB), and the G -protein-coupled melanocortin 1 receptor (MC1R), respectively. We hereby report that End-1 and α-MSH regulate common effectors of the DNA damage response to UV, despite distinct signaling pathways.

Fueling Melanocytes with ATP from Keratinocytes Accelerates Melanin Synthesis.

Melanocyte homoeostasis and their response to ultraviolet radiation (UVR) are mediated to a large extent by keratinocyte-derived factors, many of which have been well-characterized. Lee et al. describe novel effects of adenosine 5'-triphosphate (ATP), which is secreted by keratinocytes and can stimulate melanogenesis by melanocytes following UVA exposure.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease.

MC1R: Front and Center in the Bright Side of Dark Eumelanin and DNA Repair.

Melanin, the pigment produced by specialized cells, melanocytes, is responsible for skin and hair color. Skin pigmentation is an important protective mechanism against the DNA damaging and mutagenic effects of solar ultraviolet radiation (UV). It is acknowledged that exposure to UV is the main etiological environmental factor for all forms of skin cancer, including melanoma.

The potential role of antioxidants in mitigating skin hyperpigmentation resulting from ultraviolet and visible light-induced oxidative stress.

Oxidative stress is an integral element that influences a variety of biochemical reactions throughout the body and is known to play a notable role in melanogenesis. Exogenous triggers of oxidative stress, such as ultraviolet radiation (UVR) and visible light (VL), lead to pigment formation through somewhat different pathways, but both share a common endpoint-the potential to generate cosmetically undesirable hyperpigmentation. Though organic and inorganic sunscreens are available to protect against the UVR portion of the electromagnetic spectrum, coverage is lacking to protect against the VL spectrum.

Suppression of MAPK signaling in BRAF-activated PTEN-deficient melanoma by blocking β-catenin signaling in cancer-associated fibroblasts.

Cancer-associated fibroblasts (CAFs) in the tumor microenvironment have been associated with formation of a dynamic and optimized niche for tumor cells to grow and evade cell death induced by therapeutic agents. We recently reported that ablation of β-catenin expression in stromal fibroblasts and CAFs disrupted their biological activities in in vitro studies and in an in vivo B16F10 mouse melanoma model. Here, we show that the development of a BRAF-activated PTEN-deficient mouse melanoma was significantly suppressed in vivo after blocking β-catenin signaling in CAFs.

Restoration of cutaneous pigmentation by transplantation to mice of isogeneic human melanocytes in dermal-epidermal engineered skin substitutes.

Autologous engineered skin substitutes (ESS) containing melanocytes (hM) may restore pigmentation and photoprotection after grafting to full-thickness skin wounds. In this study, normal hM were isolated from discard skin, propagated with or without tyrosinase inhibitors, cryopreserved, recovered into culture, and added to ESS (ESS-P) before transplantation. ESS-P were incubated in either UCMC160/161 or UCDM1 medium, scored for hM densities, and grafted to mice.

Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity.

The membrane bound melanocortin 1 receptor (MC1R), and the endothelin B receptor (ENDBR) are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR), the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH) and adrenocorticotropic hormone (ACTH). The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET)-3 during embryonic development, and ET-1 postnatally.

Beyond Red Hair and Sunburns: Uncovering the Molecular Mechanisms of MC1R Signaling and Repair of UV-Induced DNA Damage.

Scientists at the University of Kentucky are unraveling the details of DNA-damage repair in the melanocyte, with an eye towards finding druggable targets for melanoma prevention. Jarret et al., (2015, this issue) report in this issue three new assays that can yield mechanistic information about nucleotide excision repair (NER) stimulated by cAMP-dependent signaling downstream of the melanocortin-1 receptor (MC1R).

Endothelin-1 protects human melanocytes from UV-induced DNA damage by activating JNK and p38 signalling pathways.

Endothelin-1 is a paracrine factor with mitogenic, melanogenic and survival effects on cultured human melanocytes. We report that endothelin-1 signalling reduced the generation and enhanced the repair of ultraviolet radiation (UV)-induced DNA photoproducts, and inhibited apoptosis of human melanocytes, without increasing cAMP levels, melanin content or proliferation. Treatment with endothelin-1 activated the MAP kinases JNK and p38, as evidenced by phosphorylation of their target, activating transcription factor-2 (ATF-2).