Exosomal transfer of functional small RNAs mediates cancer-stroma communication in human endometrium

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.