Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression
Abstract
:1. Introduction
2. Role of Acidic and Hypoxic Microenvironment in Melanoma
3. How Acidity and Hypoxia Modulate Melanoma Progression through Mexo
3.1. Characteristics of Mexo Released in Acidic and Hypoxic TME
3.2. Mechanisms of Progression and Metastatic Spread
4. Immune System Modulation under Acidosis and Hypoxia: Role of Mexo
5. The Use of Exo in Melanoma Diagnosis, Prognosis and Response to Treatment: Promising Studies
6. Conclusions and Future Perspectives
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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Molecule | Targets | Functional Effects | Bibliography * |
---|---|---|---|
miR-494 | BIM; PTEN | Modulates cell proliferation; promotes cell migration and invasion; enhances angiogenesis and tumour growth under hypoxic conditions. | [1,2,3] |
miR-1290 | SOCS4; LHX6; CCNG2; IKK1; NKD1; INPP4B | Promotes cell proliferation, tumour growth, metastatization and EMT; supresses apoptosis and increases resistance to chemo-radiation | [4,5,6,7,8,9,10] |
AKR7A2 | Succinic semialdehyde | Supports gamma-Hydroxybutyrate production | [11] |
DDX39B | Pre-ribosomal RNA; BRCA1 mRNA | Enhances cell proliferation and increases cell chemotherapy resistance | [12,13] |
EIF3C | PI3K/Akt/NF-κB; THBS1, RAP1A, CYR61, ADAMTS1, TUFT1, CFL2, EPHA and EPHB; WNT5B, DHH, SMO, RAC2, PCSK1N and INMBA | Promotes cell proliferation, survival, migration and invasiveness | [14,15,16] |
N.D. | Impairs the sensitivity to EGFR-TKI (Erlotinib) by enhancing the autophagic activity | [17] | |
FARSA | Activated by FARSA-AS1 | Promotes tumour growth and metastasis | [18] |
circFARSA | miR-330-5p/LASP1 | Enhance proliferation, migration, and invasion | [19] |
PMRT5 | H3R8, H4R3 and RBL2; CUL4AB promoters; PDCD4; eIF4E; E2F1; HIF-1 | Promotes cancer cell proliferation and inhibits apoptosis | [20,21,22,23,24,25] |
MDM4 | Supports drug resistance to palbociclib | [26] | |
IFI16 and NLRC5 | Impairs antitumor immune response | [27] | |
BCL6 | Regulates the germinal centre reaction | [28] | |
VARS | TCTP-EF1A2 | Promotes tumorigenesis and tumour progression | [29,30] |
hnRNP L | miR-574-3p; AXL; SRSF3; p53, Bcl-2, caspases-3, -6, -9 and MAPK; SPRY4-IT1 | Promotes cell proliferation and inhibits apoptosis, enhances tumorigenesis and the tumour metastatic potential | [31,32,33,34,35,36] |
hnRNP K | MAP 1B-LC1; SRSF1; DUSP1; EZH2-SOX2; CCND1, G0S2, XAF1 and ERCC4; MMP12 and ß-catenin; XIAP; GSN mRNA; MMP-2 | Promotes EMT, cell proliferation, migration and invasion; role in chemoresistance | [37,38,39,40,41,42,43,44] |
PTGS2, CCK3, RAS, ERK and MMP-3. | Promotes tumour metastasis regulating extracellular matrix, cell motility, and angiogenesis pathways | [45] | |
RAN | Importin-β; RhoA; Caspase-3; AR; Met and c-Met receptor; PI3 kinase; Txl-2b; AR and CXCR4; Cyclin A, Cyclin D1, Cyclin E, CDK2, CDK4, phospho-Rb and Survivin; PI3K/Akt/mTORC1 and Ras/MEK/ERK; FGF2; Aurora Kinase A; miR-21 | Enhances tumorigenesis; inhibits apoptosis; promotes cell proliferation, migration and invasion; promotes gefitinib resistance | [46,47,48,49,50,51,52,53,54,55,56] |
NRAS and HRAS | BRAF, PI3K, PLC/PKC, RAL | Promote proliferation, survival and cell growth, and enhances cell migration | [57] |
SDF-1, I-TAC, CCL9/10, and MCP5 | Induces the tumour immune escape | [58] | |
HSPA1L | IGF1Rβ and β-Catenin | Enhances EMT and Cancer Stem Cell-like properties | [59] |
HIF-1α/GP78 | Promotes the cellular prion protein (PrPC) accumulation and tumorigenicity | [60] | |
HSPA5 (GRP78) | VEGFR-2; Kringle 5 | Promotes vascularization | [61,62] |
TFEB, CSTD, CTSL, and LAMP1 | Supports cell protection against ER stress and ROS damage; regulates lysosomal activity | [63] | |
ATF4-DDIT4-mTORC1 | Induces pro-survival autophagy | [64] | |
Cripto; Proteinase inhibitor α2-macroglobulin (α2M *); FAK; PRMT7; PI3K/Akt/Mdm2 | Activates EMT and promotes cell proliferation, migration and invasion | [65,66,67,68,69] | |
Raf-1; Caspase-7; PERK; Wnt | Inhibits apoptosis and enhances cell survival | [70,71,72,73] | |
CD5L; CHOP, Bcl-2 and Bax; GPX4; ERK/AKT and BOK/NOXA | Involved in chemoresistance | [74,75,76,77] | |
IL-10, TGF-β and IDO; PD-L1; LAP/TGF-beta | Supports tumour immune escape; cell protection from CTL-mediated lysis | [78,79,80] | |
HSP90B1 (GRP94 and GP96) | Twist1 | Promotes vasculogenic mimicry | [81] |
CCT8/c-Jun; AKT and eNOS; TGF-β1; Ack1; RAC1, VAMP2, LAMP1, SYNE2, integrin α2/αL; Wnt/β-catenin | Contributes to tumorigenesis and promotes cell migration, invasion and metastasis | [82,83,84,85,86,87] | |
Mdm2 E3 ligase | Inhibits apoptosis and decreases p53 levels | [88] | |
Proteasome and MHC molecules | Participates in peptide generation and modulates immune system | [89] | |
TGF-β and SMAD2 | Induces Treg infiltration by promoting the TGF-β signalling pathway. | [90] | |
TNF-α, IL-10, IL-12 p70 and IFN-γ | Promotes T cell response, enhances DC antigen presentation and induces cytokine secretion | [91] | |
HSP90AB1 | VEGFR | Promotes endothelial tumor angiogenesis and accelerates neovascularization | [92] |
Bcl-2 | Inhibits cell apoptosis and increases the caspase activation | [93] | |
Fibronectin | Induces fibronectin exocytosis and formation of extracellular matrix | [94] | |
ERBB2 and CDK4; LRP5 | Promotes cell proliferation, invasion and migration, tolerance to chemotherapeutic drugs and in vivo metastasis | [95,96] | |
CFL2 | miR-3189-3p; miR-369-3p; miR-1299 | Enhances cell proliferation and migration; impairs tumour cell apoptosis | [97,98,99] |
GSN | Nm23-H1; MCL-1, MMP-2 and MMP-9; p-AKT and p-P38 | Promotes cell growth, migration and invasion and in vivo tumour growth | [100,101,102] |
XIAP, FLIP, Akt and AIF; PSME2, PTK2B, FOS, JUN, ITGB1, MAP2K7, MAP3K4, MAP3K12, Rac1 and RRM2B | Inhibits apoptosis; supports the response to cisplatin | [103,104] | |
TIMP3 | Tnfr1 | Supports early stage of tumorigenesis | [105] |
GANAB | Wnt/β-catenin | Promotes proliferation and suppresses apoptosis | [106,107] |
HYOU1 | LDHB mRNA; IFN-type I; CHOP; VEGF; PI3K/AKT; MMP-2 | Promotes proliferation, migration, invasion of cancer cells and inhibits apoptosis | [108,109,110,111,112,113] |
Sphingo-mielin | KRAS | Increases the growth of oncogenic K-Ras-transformed tumours | [114] |
EGFR/ErbB1 | Modulates cell motility and focal adhesion clustering | [115] |
miRNA Name | Involved Process | Oncomir | Effects | References * |
---|---|---|---|---|
hsa-let-7f-5p | Mt | No | Interferes with cell anchorage and promotes cell cycle process during metastatic expansion | [116] |
hsa-mir-10b-5p | Mt | Yes | Promotes progression and metastasis through by donwregulation of ITCH in Wnt/beta-Catenin pathway | [117] |
hsa-mir-125a-3p | Mt, Dr | No | Promotes melanoma progression and metastasis via Lin28B protein; Promotes melanoma resistance to the BRAF inhibitor Vemurafenib via suppression of apoptotic pathways | [118,119] |
hsa-mir-150-5p | Mt | No | Key regulator of proliferation, invasion and glycogenesis in malignant melanoma through SIX1 | [120] |
hsa-mir-152-3p | Mt | No | Promotes malignant melanoma progression by binding to the lncRNA HOTAIR | [121] |
hsa-mir-155-5p | Pr | No | Can increase melanoma progression by modulation of the SKI factor | [122] |
hsa-mir-181b-3p hsa-mir-181b-5p hsa-mir-181d-5p | Pr | No | Elicit melanoma cell cycle by targeting the CTDSPL protein | [123] |
hsa-mir-188-3p | Mt | No | Sustains melanoma progression via Mesenchimal Stem Cell reprogramming | [124] |
hsa-mir-191-3p hsa-mir-191-5p | Pr | No | Associated with poor survival in melanoma patients | [125] |
hsa-mir-196a-5p | Pr | No | Aberrantly expressed in melanoma by disregulation of HOX-C8 expression | [126] |
hsa-mir-199a-3p | Mt | Yes | Promotion of melanoma metastasis and angiogenesis by targeting the ApoE lipoprotein | [127] |
hsa-mir-200a-3p | Mt, Dr | No | Reduced response to CDK4/6 inhibitor in highly proliferative metastatic melanoma via diminished expression of CDK6 | [128] |
hsa-mir-200b-3p | Pr | No | Activates melanoma invasiveness, progression and EMT via the NEAT1/SMAD2 axis | [129] |
hsa-mir-203a-3p | Mt | Yes | Promotion of stemness, increased BRAF expression and augmented tumorigenesis in melanoma cell lines and in vivo | [130] |
hsa-mir-210-3p | Is | No | Promotes melanoma progression by hypoxia-induced immunosuppression in oxygen-deprived regions of the melanoma microenvironment favoring the evolution of cancer stem cells and the resistance to drug therapy | [131] |
hsa-mir-21-3p | Mt | Yes | Promotes melanoma cell invasiveness by decreasing the expression of the tissue Metalloproteinase 3 inhibitors in vivo Enhances melanoma invasion and metastasis by promoting the insurgence of NRAS and BRAF mutation and by increasing the expression of L1CAM | [132,133] |
hsa-mir-21-5p | Pr | Yes | Targets CDKN2C and activates melanoma cell progression and G1/S transition | [134] |
hsa-mir-224-5p | Mt | Yes | Induction of EMT by TXNIP downregulation | [135] |
hsa-mir-24-3p | Mt, Dr | No | Confers resistance to Vemurafenib through the occurrence of BRAF mutations in melanoma | [136] |
hsa-mir-26b-5p | Is | No | Elicits melanoma progression by favoring the HLA class I-mediated immune escape | [137] |
hsa-mir-30a-5p | Dr | No | Confers resistance to Cisplatin by targeting the IGF1R gene | [138] |
hsa-mir-30d-3p hsa-mir-30d-5p | Mt, Is | Yes | Enhances melanoma cell invasiveness and immunosuppression (via increasing Treg cells) during metastatic expansion by modulation of GalNAc transferases | [139] |
hsa-mir-373-3p | Mt, Is | Yes | Decreases immunovisibility to melanoma thus increasing tumour dissemination; Promotion of melanoma cell invasiveness by SIK1 targeting | [140,141] |
hsa-mir-93 | Mt | No | Found upmodulated in melanoma metastases | [142] |
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Boussadia, Z.; Gambardella, A.R.; Mattei, F.; Parolini, I. Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression. Cells 2021, 10, 3311. https://doi.org/10.3390/cells10123311
Boussadia Z, Gambardella AR, Mattei F, Parolini I. Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression. Cells. 2021; 10(12):3311. https://doi.org/10.3390/cells10123311
Chicago/Turabian StyleBoussadia, Zaira, Adriana Rosa Gambardella, Fabrizio Mattei, and Isabella Parolini. 2021. "Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression" Cells 10, no. 12: 3311. https://doi.org/10.3390/cells10123311
APA StyleBoussadia, Z., Gambardella, A. R., Mattei, F., & Parolini, I. (2021). Acidic and Hypoxic Microenvironment in Melanoma: Impact of Tumour Exosomes on Disease Progression. Cells, 10(12), 3311. https://doi.org/10.3390/cells10123311