Abstract
Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring.
Highlights
Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10–15% of childhood non-Hodgkin lymphomas [1]
We performed extensive research on the proteomic makeup of plasmatic small extracellular vesicles (S-extracellular vesicles (EVs)) of ALCL patients compared to healthy donors, and we propose S-EV tenascin C (TNC), osteopontin (SPP1/OPN) and heat shock protein 90-kDa isoform alpha 1 (HSP90AA1) as potential biomarkers for ALCL prognostic stratification
Out of 20) presented with disease stage III/IV, the lowest levels of S-EV SAA1 and SAA2 were detected in two patients with stage I/II, with the stage I patient showing undetectable levels of SAA2 (Table S1)
Summary
Anaplastic large-cell lymphoma (ALCL) accounts for approximately 10–15% of childhood non-Hodgkin lymphomas [1]. Despite a continuous improvement in the field of ALCL prognostic stratification, the identification of new, non-invasive disease biomarkers which might further complement those currently in use, while relying on the most relevant disease mechanisms, is still necessary In this regard, extracellular vesicles (EVs) gathered great importance both as stable biomarkers carriers and as active players in tumorigenesis. While plasma membrane-budded microvesicles are predominantly characterized as products of platelets, endothelial cells and red blood cells, S-EVs are intraluminal vesicles deriving from multivesicular bodies formed inside endosomal compartments [6] During this process, several mechanisms ensure the specific sorting of bioactive molecules into exosomes, making them the most attractive intercellular messengers among all EVs [7,8,9]. We performed extensive research on the proteomic makeup of plasmatic S-EVs of ALCL patients compared to healthy donors, and we propose S-EV tenascin C (TNC), osteopontin (SPP1/OPN) and heat shock protein 90-kDa isoform alpha 1 (HSP90AA1) as potential biomarkers for ALCL prognostic stratification
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