Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

Abstract

Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in melanoma growth, invasiveness, and response to therapy. Melanoma represents a highly aggressive and heterogeneous type of skin cancer. Currently employed treatments, including BRAF V600E inhibitors and immune therapy, often are not effective due to a rapidly developing drug resistance. A variety of intracellular mechanisms impeding the treatment were discovered. However, the tumor microenvironment encompassing stromal and immune cells, extracellular matrix, and physicochemical conditions such as oxygen level or acidity, may also influence the therapy effectiveness. Hypoxia and acidification are able to reprogram the metabolism of melanoma cells, enhance their survival and invasiveness, as well as promote the immunosuppressive environment. For this reason, these physicochemical features of the melanoma niche and signaling pathways related to them emerge as potential therapeutic targets.

Keywords: acidification; drug resistance; hypoxia; immune escape; invasiveness; melanoma; tumor microenvironment.

Figure 1

Influence of hypoxia on melanoma progression. Detailed descriptions can be found in the text. Abbreviations: miR, microRNA; MHC I, major histocompatibility complex class I; HMGB1, high mobility group box 1 protein; IL-8, interleukin 8; VEGF, vascular endothelial growth factor; RLIP76, Ral-interacting protein of 76 kDa; Bcl-2, B-cell CLL/lymphoma 2; BNIP3, Bcl-2 interacting protein 3; HIF-1α, hypoxia-inducible factor 1 α; Mcl-1, myeloid cell leukemia 1; BAD, Bcl-2-associated agonist of cell death; AKAP12v2, A-kinase anchor protein 12 variant 2; MMP2, matrix metalloproteinase 2; LRIG1, leucine-rich repeats and Ig-like domains 1; MITF, microphthalmia-associated transcription factor; GM-3, monosialodihexosylganglioside.

Figure 2

Influence of extracellular acidification on melanoma progression. Detailed descriptions can be found in the text. Abbreviations: NHE, Na/H exchanger; MCT, monocarboxylate transporters; PPP, pentose phosphate pathway; CA, carbonic anhydrase; N-cad, N-cadherin; NF-κB, nuclear factor-kappa B; E-cad, E-cadherin; KLF4, Krüppel-like factor 4; OCT4, octamer-binding transcription factor 4; SOX2, SRY-box transcription factor 2; ALDH, aldehyde dehydrogenase; MMP, matrix metalloproteinase; MITF, microphthalmia-associated transcription factor; VEGF, vascular endothelial growth factor; IL-8, interleukin 8; EMT, epithelial-to-mesenchymal transition.