Expression of the αVβ3 integrin affects prostate cancer sEV cargo and density and promotes sEV pro-tumorigenic activity in vivo through a GPI-anchored receptor, NgR2.

Autor: Verrillo CE; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Quaglia F; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Shields CD; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Lin S; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Kossenkov AV; Bioinformatics Shared Resource, Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, Pennsylvania, USA., Tang HY; Proteomics and Metabolomics Shared Resource, The Wistar Institute, Philadelphia, Pennsylvania, USA., Speicher D; Proteomics and Metabolomics Shared Resource, The Wistar Institute, Philadelphia, Pennsylvania, USA., Naranjo NM; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Testa A; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Kelly WK; Department of Medical Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Liu Q; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA., Leiby B; Division of Biostatistics, Department of Pharmacology, Physiology, and Cancer Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA., Musante L; Extracellular Vesicle Core, PennVet, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Sossey-Alaoui K; Department of Medicine, Case Western Reserve University, School of Medicine MetroHealth Medical Center Rammelkamp Center for Research, Cleveland, Ohio, USA., Dogra N; Department of Pathology and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Chen TY; Department of Pathology and Cell Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA., Altieri DC; Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania, USA., Languino LR; Prostate Cancer Discovery and Development Program, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.; Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: Journal of extracellular vesicles [J Extracell Vesicles] 2024 Aug; Vol. 13 (8), pp. e12482.
DOI: 10.1002/jev2.12482
Abstrakt: It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low-density sEV subpopulation. This low-density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell-derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.
(© 2024 The Author(s). Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.)
Databáze: MEDLINE
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