Page 13 - TD-4-2

Tumor Discovery Melanoma exosomes in metastasis

1. Introduction including immune modulation, interaction with the
tumor microenvironment (TME), and the facilitation
Melanoma is a cancer that originates from pigment- of epithelial-to-mesenchymal transition (EMT). The
26
1
producing cells in the skin. It is known for its aggressive molecular cargos of melanoma-derived exosomes, such
behavior, high propensity for metastasis, and increasing as specific DNA, miRNAs, and lncRNAs, have significant
incidence rates worldwide, particularly among young potential as indicators for early diagnosis and predictors
2
adults. The American Cancer Society reports that of treatment outcomes. Furthermore, modified exosomes
melanoma is a leading cause of skin cancer-related deaths, offer a groundbreaking solution for targeted drug
with an estimated 99,780 new cases and 7650 fatalities in administration, enabling precision medicine approaches
the United States in 2022. The disease is classified into that minimize systemic toxicity.
3
several types, including cutaneous melanoma, mucosal
4
melanoma, and uveal melanoma, each presenting This review aims to provide a comprehensive summary
unique challenges in terms of diagnosis, treatment, and of current knowledge regarding tumor-derived exosomes
prognosis. 5-12 and their role in metastasis, based on literature from
The metastatic process in melanoma is complex and the National Library of Medicine, National Center for
involves several steps: local tissue invasion, entry into the Biotechnology Information (https://www.ncbi.nlm.nih.
bloodstream or lymphatic system, persistence in circulation, gov/). We explore the biogenesis and composition of
migration into distant tissues, and establishment at melanoma-derived exosomes, their functional implications
secondary sites. Common sites of metastasis include in metastasis, and their potential as clinical diagnostics
13
nearby lymph nodes, pulmonary tissue, hepatic tissue, and targeted therapies. By integrating recent findings in
and the brain. The prognosis for patients with metastatic exosome research with the broader context of melanoma
14
melanoma remains poor, with a 5-year survival rate of biology, we aim to highlight the significance of exosomes in
<30%. Although significant progress has been made with shaping the metastatic landscape of melanoma and identify
15
treatments such as immunotherapy and targeted therapies future directions for research and clinical application.
addressing specific genetic mutations, many patients still This review covers several key aspects related to
16
experience disease recurrence and progression. 17 melanoma-derived exosomes: (i) the biogenesis and
Melanoma cells utilize key molecular pathways, composition of exosomes; (ii) the cargos of exosomes,
such as the mitogen-activated protein kinase and including nucleic acids, proteins, lipids, and metabolites;
phosphoinositide 3-kinase-protein kinase B signaling (iii) the functional implications of exosomes, particularly
cascades, to drive invasive behavior and survival during their involvement in processes such as proliferation,
metastasis. In addition, immune evasion mechanisms, migration, invasion, immune modulation, and TME
18
including the suppression of cytotoxic T-cell responses remodeling; and (iv) the potential use of exosomes in
through programmed death-ligand 1 (PD-L1) expression, diagnosis and treatment, including their role as biomarkers,
19
further facilitate the metastatic cascade. During this therapeutic targets, and drug delivery systems.
process, melanoma-derived exosomes play a pivotal role
in preparing distant organs for tumor colonization by 2. Exosome biogenesis and composition
modulating the local microenvironment. These vesicles Exosomes are formed through the endosomal pathway,
deliver pro-inflammatory cytokines, extracellular matrix where inward budding of the endosomal membrane
(ECM) remodeling enzymes, and angiogenic factors to generates multivesicular bodies (MVBs). 27,28 Exosomes
distant tissues, fostering a permissive niche for tumor cell exhibit significant heterogeneity in size, molecular
invasion. composition, and biological functions, which complicates
Recent studies have emphasized the pivotal role their characterization and therapeutic applications.
of exosomes in cancer development, particularly in Advanced separation techniques, such as asymmetric-
metastasis. 20-22 Exosomes, small extracellular vesicles flow field-flow fractionation, have identified distinct
(30 – 150 nm), originate from the endosomal membrane extracellular nanoparticle subpopulations, including large
and are secreted into the extracellular space. 23,24 These exosome vesicles (Exo-L, 90 – 120 nm), small exosome
vesicles transport biomolecules, such as proteins, lipids, vesicles (Exo-S, 60 – 80 nm), and exomeres (~35 nm, non-
27
and nucleic acids (DNA, long noncoding RNAs [lncRNAs], membranous nanoparticles). These subtypes carry unique
and microRNAs [miRNAs]), reflecting the molecular proteomic, lipidomic, and transcriptomic signatures,
traits of their source cells. In melanoma, exosomes influencing their roles in tumor progression, immune
25
actively participate in a wide range of biological processes modulation, and organotropic metastasis. Traditional
that contribute to tumor progression and metastasis, isolation methods, such as ultracentrifugation and size-

Volume 4 Issue 2 (2025) 5 doi: 10.36922/td.7108