Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression

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.

Antitumor Activity of the Zinc Oxide Nanoparticles Coated with Low-Molecular-Weight Heparin and Doxorubicin Complex In Vitro and In Vivo

“…Acidity is a unique hallmark of the tumor microenvironment. − Many pH-sensitive nanomedicines were designed and prepared to respond to the acidic tumor microenvironment promoting antitumor efficiency. − Inorganic nanomaterials, which possess a diverse range of structure, composition, morphology, and physicochemical properties have been used in cancer treatment and diagnosis as delivery carriers. − Recently, various metal oxides or calcium-based nanomaterials have been widely used as pH-sensitive inorganic nanomaterials. − It has been reported that ZnO NPs could be used as pH-responsive drug carriers, which possess pH-triggered drug release characteristics displaying a response to acid and a rapid dissolution to Zn 2+ at pH <5.5, especially in lysosomes used for intracellular drug delivery platforms. − The intracellular Zn 2+ produced by ZnO NPs has cytotoxic effects in tumor cells. , In addition, ZnO NPs could significantly induce the generation of ROS in tumor cells. − In particular, ZnO NPs can make full utilization of disproportional reaction, Haber–Weiss reaction, or Fenton reaction to compensate for O 2 -depletion, thus greatly improving the therapeutic efficacy against hypoxic tumors . ZnO NPs also have good optical properties and high stability to be a promising candidate for bioimaging. , ZnO NPs could be used to in situ upconvert NIR to visible light through the second harmonic generation (SHG) mechanism for tumor imaging. , Recently, we designed an H 2 O 2 -triggered intelligent photodynamic therapy (PDT) nano delivery system, LCL/ZnO, that could selectively regulate the tumor-derived endothelial cells (TECs) and specifically kill tumor cells by producing different singlet oxygen ( 1 O 2 ) in response to different H 2 O 2 gradients in TECs and tumor cells .…”

The prognostic marker elastin correlates with epithelial–mesenchymal transition and vimentin‐positive fibroblasts in gastric cancer

“…Fibroblasts accumulate in the TME and contribute to the emergence and progression of GC [ 19 , 20 ]. This not only provides abundant growth factors for stromal components of the TME and promotes the proliferation of cancer cells but also creates a suitable physical environment for lymphatic metastasis and blood metastasis of cancer cells [ 21 , 22 , 23 ].…”

Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy

“…Melanoma-derived exosomes containing miR-155 and miR-210 were shown to reprogram dermal fibroblasts by increasing aerobic glycolysis and reducing oxidative phosphorylation, which led to extracellular acidification [ 62 ]. The role played by melanoma-derived EVs under acidic and hypoxic conditions has been recently reviewed [ 63 ].…”