1. Plasma-Derived Extracellular Vesicles and Non-Extracellular Vesicle Components from APC Min/+ Mice Promote Pro-Tumorigenic Activities and Activate Human Colonic Fibroblasts via the NF-κB Signaling Pathway.
- Author
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Arteaga-Blanco LA, Evans AE, and Dixon DA
- Subjects
- Animals, Humans, Mice, Adenomatous Polyposis Coli Protein metabolism, Adenomatous Polyposis Coli Protein genetics, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Carcinogenesis pathology, Carcinogenesis genetics, Carcinogenesis metabolism, Colon pathology, Colon metabolism, Colorectal Neoplasms pathology, Colorectal Neoplasms metabolism, Colorectal Neoplasms genetics, Cytokines metabolism, Mice, Inbred C57BL, Tumor Microenvironment, Extracellular Vesicles metabolism, Fibroblasts metabolism, NF-kappa B metabolism, Signal Transduction
- Abstract
Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Current studies have demonstrated that tumor-derived extracellular vesicles (EVs) from different cancer cell types modulate the fibroblast microenvironment to contribute to cancer development and progression. Here, we isolated and characterized circulating large EVs (LEVs), small EVs (SEVs) and non-EV entities released in the plasma from wild-type (WT) mice and the APC
Min/+ CRC mice model. Our results showed that human colon fibroblasts exposed from APC-EVs, but not from WT-EVs, exhibited the phenotypes of cancer-associated fibroblasts (CAFs) through EV-mediated NF-κB pathway activation. Cytokine array analysis on secreted proteins revealed elevated levels of inflammatory cytokine implicated in cancer growth and metastasis. Finally, non-activated cells co-cultured with supernatant from fibroblasts treated with APC-EVs showed increased mRNA expressions of CAFs markers, the ECM, inflammatory cytokines, as well as the expression of genes controlled by NF-κB. Altogether, our work suggests that EVs and non-EV components from APCMin/+ mice are endowed with pro-tumorigenic activities and promoted inflammation and a CAF-like state by triggering NF-κB signaling in fibroblasts to support CRC growth and progression. These findings provide insight into the interaction between plasma-derived EVs and human cells and can be used to design new CRC diagnosis and prognosis tools.- Published
- 2024
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