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by claude@2026-06, 2026-06-24
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The study investigated how melanoma-derived large extracellular vesicles (L-EVs) influence endothelial angiogenic behavior, including how this affects resistance to bevacizumab. Using endothelial tube-formation assays, the authors found that melanoma L-EVs promote bevacizumab-insensitive angiogenic phenotypes, with the effect blocked by sorafenib but not by SU5416; they also identified VEGF as luminal cargo within L-EVs and showed that L-EVs modulate the endothelial EV secretome. The paper further reports that soluble VEGF, EVs, and pro-angiogenic cytokines (IL-8, MIF, and PAI-1) from endothelial cells support sustained tube formation via autocrine signaling, and that EV subtypes produce distinct angiogenic effects that vary by tumor type. A stated caveat is that the work focuses on melanoma-derived L-EVs and endothelial tube-formation phenotypes as mechanistic readouts, rather than broader in vivo outcomes across contexts. This paper does not explicitly discuss endometriosis or adenomyosis; it was included in the corpus via a keyword match in the upstream search index.
Abstract
Angiogenesis, a process typically associated with tumor growth and development, is often linked to advanced disease and poor clinical outcomes. Tumor cells establish a pro-angiogenic microenvironment through the release of paracrine signaling mediators including extracellular vesicles (EVs). EVs have been shown to facilitate intercellular communication and encompass a diverse range of secreted vesicles, including small EVs (sEVs) which range in size from ∼60 to 100nm and large EVs (L-EVs) which are even more diverse and range from 200nm to >1μm in size. Despite advancements in anti-angiogenic cancer therapies, such as bevacizumab, late-stage tumors, including advanced melanomas, exhibit mixed clinical responses. In this study, we elucidate a unique role for melanoma-derived L-EVs in promoting bevacizumab-insensitive endothelial angiogenic phenotypes. This L-EV-mediated increase in endothelial tube formation is sensitive to the effects of sorafenib, a multi-kinase inhibitor, but not SU5416, a selective VEGF-receptor inhibitor. We also demonstrate that melanoma L-EVs contain VEGF as luminal cargo and induce paracrine effects by modulating the endothelial EV secretome. The release from endothelial cells of soluble VEGF, EVs, and pro-angiogenic cytokines such as IL-8, MIF, and PAI-1 drive sustained endothelial tube formation through autocrine signaling. Finally, we show that EV subtypes have distinct effects on the acquisition of angiogenic phenotypes and their roles vary with tumor type. These findings provide new insight into the mechanisms of angiogenic therapy resistance in melanoma and demonstrate the differential functions of EV subtypes in angiogenesis across tumor types.
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Abstract
Angiogenesis, a process typically associated with tumor growth and development, is often linked to advanced disease and poor clinical outcomes. Tumor cells establish a pro-angiogenic microenvironment through the release of paracrine signaling mediators including extracellular vesicles (EVs). EVs have been shown to facilitate intercellular communication and encompass a diverse range of secreted vesicles, including small EVs (sEVs) which range in size from ∼60 to 100nm and large EVs (L-EVs) which are even more diverse and range from 200nm to >1μm in size. Despite advancements in anti-angiogenic cancer therapies, such as bevacizumab, late-stage tumors, including advanced melanomas, exhibit mixed clinical responses. In this study, we elucidate a unique role for melanoma-derived L-EVs in promoting bevacizumab-insensitive endothelial angiogenic phenotypes. This L-EV-mediated increase in endothelial tube formation is sensitive to the effects of sorafenib, a multi-kinase inhibitor, but not SU5416, a selective VEGF-receptor inhibitor. We also demonstrate that melanoma L-EVs contain VEGF as luminal cargo and induce paracrine effects by modulating the endothelial EV secretome. The release from endothelial cells of soluble VEGF, EVs, and pro-angiogenic cytokines such as IL-8, MIF, and PAI-1 drive sustained endothelial tube formation through autocrine signaling. Finally, we show that EV subtypes have distinct effects on the acquisition of angiogenic phenotypes and their roles vary with tumor type. These findings provide new insight into the mechanisms of angiogenic therapy resistance in melanoma and demonstrate the differential functions of EV subtypes in angiogenesis across tumor types.
Competing Interest Statement
The authors have declared no competing interest.
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