Abstract
The mechanisms of melanoma progression have been extensively studied in the last decade, and despite the diagnostic and therapeutic advancements pursued, malignant melanoma still accounts for 60% of skin cancer deaths. Therefore, research efforts are required to better define the intercellular molecular steps underlying the melanoma development. In an attempt to represent the complexity of the tumour microenvironment (TME), here we analysed the studies on melanoma in acidic and hypoxic microenvironments and the interactions with stromal and immune cells. Within TME, acidity and hypoxia force melanoma cells to adapt and to evolve into a malignant phenotype, through the cooperation of the tumour-surrounding stromal cells and the escape from the immune surveillance. The role of tumour exosomes in the intercellular crosstalk has been generally addressed, but less studied in acidic and hypoxic conditions. Thus, this review aims to summarize the role of acidic and hypoxic microenvironment in melanoma biology, as well as the role played by melanoma-derived exosomes (Mexo) under these conditions. We also present a perspective on the characteristics of acidic and hypoxic exosomes to disclose molecules, to be further considered as promising biomarkers for an early detection of the disease. An update on the use of exosomes in melanoma diagnosis, prognosis and response to treatment will be also provided and discussed.
Highlights
Cutaneous melanoma (CM) originates from melanocytes resident in the skin and accounts for more than 90% of all melanoma cases registered in the United States, including uveal or mucosal melanoma [1]
In an attempt to represent the complexity of the tumour microenvironment (TME), here we analysed the studies on melanoma in acidic and hypoxic microenvironments and the interactions with stromal and immune cells
Recent studies reported a role of melanoma-derived exosomes (Mexo) in the switch from normal fibroblast (NF) to cancer associated fibroblasts (CAFs), in turn releasing cell function through the release of exosomes (CAFexo) [89] that are able to affect the phenotype of melanoma cells into the TME (Figure 2)
Summary
Cutaneous melanoma (CM) originates from melanocytes resident in the skin and accounts for more than 90% of all melanoma cases registered in the United States, including uveal or mucosal melanoma [1]. The extracellular pH (pHe) decreases to as low as 6.5, a value that is toxic to normal cells, whereas cancer cells adapt and survive [10,11,12] In this context, the increased metabolic need of tumour cells cannot be accomplished by higher oxygen consumption, due to the altered angiogenesis and to the shift from oxidative phosphorylation (OXPHOS) in the mitochondria towards glycolysis [13]. Hypoxia can induce proteomic changes that initiate cell cycle arrest, differentiation, necrosis, apoptosis [14], and may stimulate tumour growth, invasion, and metastasis [15] In these environmental conditions, the tumor mass increase is due to an impaired immune surveillance. Tumour cells use an indirect and vesicles-based mechanism to affect either the growth of tumour mass or the immune cells surveillance. We will highlight molecules (proteins, miRNAs) found upregulated in Exo under acidic and hypoxic conditions, in cell culture or patient plasma and we will discuss their potential use as biomarkers
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