Abstract
Exosomes are small membrane vesicles secreted from a variety of cell types. Recent evidence indicates that human cells communicate with each other by exchanging exosomes. Cancer cells closely interact with neighboring stromal cells, and together they cooperatively promote disease via bidirectional communication. Here, we investigated whether exosomes can play roles in intercellular communication between cancer cells and neighboring fibroblasts. Endometrial fibroblasts were isolated from normal endometrial tissues and from endometrial cancer tissues, and cell-to-cell transfer of endometrial cancer cell line Ishikawa-derived exosomes was examined. The isolated fibroblasts were cultured in conditioned media from CD63-GFP-expressing Ishikawa cells, and we found that GFP-positive exosomes were transferred from Ishikawa cells to the fibroblasts. Next, we introduced a shRNA for a luciferase gene into Ishikawa cells. This shRNA was encapsulated into exosomes, was transferred to the fibroblasts, and then downregulated luciferase expression in the fibroblasts. The mature microRNAs naturally expressed in Ishikawa-derived exosomes were also transported into the endometrial fibroblasts, and they altered the microRNA expression profiles of the fibroblasts. These results indicated that endometrial cancer cells could transmit small regulatory RNAs to endometrial fibroblasts via exosomes. Our findings document a previously unknown mode of intercellular communication between cancer cells and related fibroblasts in human endometrium.
Highlights
Progression of carcinoma is not solely achieved by malignant epithelial cells; the surrounding tumor stroma is involved in advance of the disease [1, 2]
A fusion protein comprised of CD63 and copepod green fluorescent protein (copGFP) (CD63-copGFP) was transduced into Ishikawa cells to prepare donor cells that produced copGFP-labeled exosomes, and the conditioned medium from the cells was used for the subsequent experiments
The results clearly indicated that both normal endometrial fibroblasts and endometrial cancer-derived fibroblasts were capable of incorporating small RNAs from Ishikawa-derived exosomes
Summary
Progression of carcinoma is not solely achieved by malignant epithelial cells; the surrounding tumor stroma is involved in advance of the disease [1, 2]. Fibroblasts are the most abundant cell type in tumor stroma They alter extracellular matrix composition, promote angiogenesis, and mediate the inflammatory responses. These effects contribute to progression and even initiation of carcinomas [2,3,4]. Exosomes are extracellular membrane vesicles secreted from almost all human cell types [8, 9]. They are formed through inward budding of endosomal membranes; this results in the accumulation of intraluminal vesicles within multivesicular bodies (MVBs).
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