No abstract

Skin pigmentary abnormalities are seen as aesthetically unfavorable and have led to the development of cosmetic and therapeutic treatment modalities of varying efficacy. Hence, several putative depigmenting agents aimed at modulating skin pigmentation are currently being researched or sold in commercially available products. In this review we will discuss the regulation of processes that control skin complexion coloration. This includes direct inhibition of tyrosinase and related melanogenic enzymes, regulation of melanocyte homeostasis, alteration of constitutive and facultative pigmentation and down-regulation of melanosome transfer to the keratinocytes. These various processes, in the complex mechanism of skin pigmentation, can be regulated individually or concomitantly to alter complexion coloration and thus ameliorate skin complexion diseases.

Significant regional variations in biomechanical properties and dominant side effects were observed. The biomechanical properties were significantly influenced by age. Certain properties varied with dermal thickness and tissue composition. The parameters were well correlated between the two instruments. The Cutometer, with its smaller aperture, was found to be more sensitive to age relationships.

Melanoma is known as an exceptionally aggressive and treatment-resistant human cancer. Although a great deal of progress has been made in the past decade, including the development of immunotherapy using immune checkpoint inhibitors and targeted therapy using BRAF, MEK or KIT inhibitors, treatment for unresectable stage III, stage IV, and recurrent melanoma is still challenging with limited response rate, severe side effects and poor prognosis, highlighting an urgent need for discovering and designing more effective approaches to conquer melanoma. Melanoma is not only driven by malignant melanocytes, but also by the altered communication between neoplastic cells and non-malignant cell populations, including fibroblasts, endothelial and inflammatory cells, in the tumor stroma. Infiltrated and surrounding fibroblasts, also known as cancer-associated fibroblasts (CAFs), exhibit both phenotypical and physiological differences compared to normal dermal fibroblasts. They acquire properties of myofibroblasts, remodel the extracellular matrix (ECM) and architecture of the diseased tissue and secrete chemical factors, which all together promote the transformation process by encouraging tumor growth, angiogenesis, inflammation and metastasis and contribute to drug resistance. A number of in vitro and in vivo experiments have shown that stromal fibroblasts promote melanoma cell proliferation and they have been targeted to suppress tumor growth effectively. Evidently, a combination therapy co-targeting tumor cells and stromal fibroblasts may provide promising strategies to improve therapeutic outcomes and overcome treatment resistance. A significant benefit of targeting CAFs is that the approach aims to create a tumor-resistant environment that inhibits growth of melanomas carrying different genetic mutations. However, the origin of CAFs and precise mechanisms by which CAFs contribute to melanoma progression and drug resistance remain poorly understood. In this review, we discuss the origin, activation and heterogeneity of CAFs in the melanoma tumor microenvironment and examine the contributions of stromal fibroblasts at different stages of melanoma development. We also highlight the recent progression in dissecting and characterizing how local fibroblasts become reprogrammed and build a dynamic yet optimal microenvironment for tumors to develop and metastasize. In addition, we review key developments in ongoing preclinical studies and clinical applications targeting CAFs and tumor-stroma interactions for melanoma treatment.