Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Research Program Cancer Signaling and Microenvironment, Fox Chase Institute for Cancer Research, Philadelphia, PA, USA.
Cell Rep. 2024 Sep 24;43(9):114721. doi: 10.1016/j.celrep.2024.114721. Epub 2024 Sep 9.
Advancing age is a negative prognostic factor for cutaneous melanoma. However, the role of extracellular vesicles (EVs) within the melanoma tumor microenvironment (TME) has remained unexplored in the context of aging. While the size and morphology of the EVs isolated from young vs. aged fibroblasts remained unaltered, the contents of the protein cargo were changed. Aging reduced the expression of the tetraspanin CD9 in both the dermal fibroblasts and released EVs. CD9 is a crucial regulator of EV cargo sorting. Modulating the CD9 expression in fibroblasts was sufficient to alter its levels in EVs. Mass spectrometry analysis of EVs released by CD9 knockdown (KD) vs. control cells revealed a significant increase in angiopoietin-like protein 2 (ANGPTL2), an angiogenesis promoter. Analysis of primary endothelial cells confirmed increased sprouting under CD9 KD conditions. Together, our data indicate that aged EVs play an important role in promoting a tumor-permissive microenvironment.
年龄增长是皮肤黑色素瘤的一个负性预后因素。然而，在衰老背景下，细胞外囊泡（EVs）在黑色素瘤肿瘤微环境（TME）中的作用仍未被探索。尽管从小鼠和老年成纤维细胞中分离出的 EVs 的大小和形态保持不变，但蛋白货物的含量发生了变化。衰老降低了真皮成纤维细胞和成纤维细胞释放的 EVs 中四跨膜蛋白 CD9 的表达。CD9 是 EV 货物分拣的关键调节因子。调节成纤维细胞中 CD9 的表达足以改变 EV 中 CD9 的水平。对 CD9 敲低（KD）与对照细胞释放的 EVs 进行质谱分析显示，血管生成促进因子血管生成素样蛋白 2（ANGPTL2）的水平显著增加。对原代内皮细胞的分析证实，在 CD9 KD 条件下，血管生成增加。综上所述，我们的数据表明，衰老的 EVs 在促进肿瘤有利的微环境中发挥重要作用。
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