Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts

• Published in: Gynecologic oncology 2011-11, Vol.123 (2), p.379-386
• Main Authors: Cho, Jung Ah, Park, Ho, Lim, Eun Hye, Kim, Kye Hyun, Choi, Joong Sub, Lee, Jung Hoon, Shin, Jae Wook, Lee, Kyo Won
• Format: Article
• Language: English
• Subjects: Adipose Tissue - cytology; Adipose tissue-derived stem cells; Cell Line, Tumor; Exosomes - physiology; Female; Hematology, Oncology and Palliative Medicine; Humans; Mesenchymal stem cells; Mesenchymal Stromal Cells - cytology; Myofibroblast; Myofibroblasts - physiology; Obstetrics and Gynecology; Ovarian Neoplasms - pathology; Phosphatidylinositol 3-Kinases - physiology; Receptors, Transforming Growth Factor beta - analysis; Smad2 Protein - physiology; Tumor microenvironment; Tumor stroma; Tumor-derived exosomes
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2011.08.005

Abstract Objective Most tumor tissue is composed of parenchymal tumor cells and tumor stroma. Mesenchymal stem cells (MSCs) can function as precursors for tumor stromal cells, including myofibroblasts, which provide a favorable environment for tumor progression. A close relationship between tumor cells and MSCs in a tumor microenvironment has been described. Exosomes are small membrane vesicles that are enriched with a discrete set of cellular proteins, and are therefore expected to exert diverse biological functions according to cell origin. Methods In the current study, we determined the biological effect of exosomes from two ovarian cancer cell lines (SK-OV-3 and OVCAR-3) on adipose tissue-derived MSCs (ADSCs). Results Exosome treatment induced ADSCs to exhibit the typical characteristics of tumor-associated myofibroblasts, with increased expression of α-SMA, and also increased expression of tumor-promoting factors (SDF-1 and TGF-β). This phenomenon was correlated with an increased expression of TGF-β receptors I and II. Analysis of TGF-β receptor-mediated downstream signaling pathways revealed that each exosome activated different signaling pathways, showing that exosomes from SK-OV-3 cells increased the phosphorylated form of SMAD2, which is essential in the SMAD-dependent pathway, whereas exosomes from OVCAR-3 cells increased the phosphorylated form of AKT, a representative SMAD-independent pathway. Taken together, exosomes from ovarian cancer cells induced the myofibroblastic phenotype and functionality in ADSCs by activating an intracellular signaling pathway, although the activated pathway could differ from exosome-to-exosome. Conclusion The current study suggested that ovarian cancer-derived exosomes contribute to the generation of tumor-associated myofibroblasts from MSCs in tumor stroma.