Hypoxia-dependent drivers of melanoma progression

Abstract

Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.

Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis

“…However, HIF-1a was not restricted to hypoxic regions. As previously reported, the expression of HIF-1a in cells grown under normoxic conditions and in well-vascularized regions demonstrated the correlation of this protein, and more generally of its target genes, at the beginning of CM growth; when hypoxic areas are not yet obvious (29). After uveal melanoma cells were exposed to hypoxia, the expression and nuclear localization of HIF-1a increased, targeting VEGF genes, including VEGF-A, for its transcription (31,32).…”

“…As reported for CM, hypoxia regulates the main signaling pathways involved in tumor progression and resistance to therapies. Many studies reported the essential role of hypoxia in regulating angiogenesis, VM, and response to therapy in melanoma ( 29 ). Hypoxia-inducible factors (HIFs), as a group of transcriptional activators, have emerged as the main regulators of these hypoxia-regulated angiogenic stimulators ( 30 ).…”

Heterogeneity of Melanoma Cell Responses to Sleep Apnea-Derived Plasma Exosomes and to Intermittent Hypoxia

“…In the United States, cutaneous melanoma rates (the most aggressive skin tumor type) have continuously increased over the last two decades, and continue to increase. In the framework of OSA, in addition to the aforementioned epidemiological evidence, several studies using animal models to study melanoma tumor growth [ 14 , 15 ], metastasis [ 12 ] and potential interactions with obesity [ 16 ] confirmed that intermittent hypoxia mimicking the oscillations in oxygen tension that characterize OSA induce significant changes in the biological properties of melanoma cells, thereby promoting accelerated proliferation, invasion and resistance to therapy [ 12 , 16 , 17 , 18 , 19 , 20 , 21 ]. However, it has also become apparent that there is considerable variability in the response to hypoxia by any type of malignant tumor, and that such heterogeneity may account for the conflicting findings in epidemiological studies attempting to link between OSA and cancer [ 22 ].…”

Special Issue “Precision Oncology in Melanoma Progression”

“…Melanoma represents the most malignant type of skin cancer, with increasing incidence worldwide. Melanoma malignancy originates from pigment-producing melanocytes in the skin (cutaneous melanoma), in the choroid, ciliary body and iris of the eye (uveal melanoma) or in mucosal membranes from different sites (mucosal melanoma) [ 1 ]. Cutaneous melanoma (here referred simply as melanoma) is the most studied subtype among the three.…”

“…Cutaneous melanoma (here referred simply as melanoma) is the most studied subtype among the three. Different predisposing factors to melanoma development have been reported, such as exposure to ultraviolet light radiation from sunlight, congenital and acquired melanocytic nevi, genetic susceptibility and family history [ 1 ]. As concerning somatic genetic alteration associated to melanoma, 40–50% of all melanoma patients harbor an activating BRAF mutation (mostly BRAF V600E), 20–30% NRAS mutations, 10–15% NF1 mutations and 1–3% KIT mutations [ 2 ].…”