Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis

Abstract

Secreted extracellular vesicles (EVs) are lipid bilayer particles without functional nucleus naturally released from cells which constitute an intercellular communication system. There is a broad spectrum of vesicles shed by cells based on their physical properties such as size (small EVs and large EVs), biogenesis, cargo and functions, which provide an increasingly heterogenous landscape. In addition, they are involved in multiple physiological and pathological processes. In cancer, EV release is opted by tumor cells as a beneficial process for tumor progression. Cutaneous melanoma is a cancer that originates from the melanocyte lineage and shows a favorable prognosis at early stages. However, when melanoma cells acquire invasive capacity, it constitutes the most aggressive and deadly skin cancer. In this context, extracellular vesicles have been shown their relevance in facilitating melanoma progression through the modulation of the microenvironment and metastatic spreading. In agreement with the melanosome secretory capacity of melanocytes, melanoma cells display an enhanced EV shedding activity that has contributed to the utility of melanoma models for unravelling EV cargo and functions within a cancer scenario. In this review, we provide an in-depth overview of the characteristics of melanoma-derived EVs and their role in melanoma progression highlighting key advances and remaining open questions in the field.

Keywords: extracellular vesicles; melanoma; melanosomes; metastasis; microenvironment; pre-metastatic niche; vesicular cargo.

FIGURE 1

Melanoma-secreted EV cargo. The components of the heterogeneous cargo of melanoma EVs comprise membrane proteins such as tetraspanins, integrins, melanoma antigens, CD133, Fas ligand (FasL), immune checkpoint proteins such as PD-L1 and antigen-presenting complexes such as MHC-I. In addition, EVs can contain other proteins including metaloproteinases (MMPs), oncogenes, RAB proteins, heat shock proteins (HSPs) and annexins. Several types of nucleic acid species such as DNA, messenger RNA (mRNA), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) together with lipids, and metabolites are also shuttled in melanoma EVs. Most of the information about the EV cargo has been obtained from the analysis of sEVs.

FIGURE 2

Melanocyte and keratinocytes communicate through EVs. Exposure to UV light induces among other responses the release of EVs from keratinocytes that are taken up by surrounding melanocytes. This EV release is induced by platelet-activating factor (PAF). Keratinocyte-derived cargo contains miRNAs such as miR-203 and miR-3196 that promote the upregulation of the melanogenesis master regulator MITF and other genes involved in the process such as Tyrosinase (TYR). Melanin is subsequently secreted in melanosomes to the epidermis and taken up by near-by keratinocytes. In addition, melanosome contains other cargo that induce anti-apoptotic signals in recipient cells through the upregulation of miR-21.

FIGURE 3

Main outcomes of EV release in melanoma progression. Melanoma cells secrete a variety of EVs including melanosomes, exosomes (Exos), microvesicles (MVs) and extracellular particles (EPs). Secreted vesicles target different stromal and immune populations in the tumor microenvironment and influence their phenotypic behaviour. The main effects induced by melanoma EVs in the tumor milieu include immune tolerance, angiogenesis and CAF formation. EVs also promote phenotypic changes in the tumor draining lymph nodes, the bone marrow and distant organs sucn as the lung contributing to the formation of efficient pre-metastatic niches that facilitate metastatic colonization by melanoma cells. BMPC, bone marrow progenitor cells; CAF, cancer-associated fibroblasts; ECM, extracellular matrix; MDSC, myeloid-derived suppressor cells; TAM, tumor-associated macrophages; Tregs, regulatory T-cells; uPAR, urokinase plasminogen activator surface receptor.