J Cancer 2014; 5(7):572-584. doi:10.7150/jca.8865

Research Paper

Characterization of Cancer Stem-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Transformed by Tumor-Derived Extracellular Vesicles

Ting Yan1, Akifumi Mizutani1✉, Ling Chen2, Mai Takaki1, Yuki Hiramoto1, Shuichi Matsuda1, Tsukasa Shigehiro1, Tomonari Kasai1, Takayuki Kudoh1, Hiroshi Murakami1, Junko Masuda1, Mary J. C. Hendrix3, Luigi Strizzi3, David S. Salomon4, Li Fu5, Masaharu Seno1✉

1. Department of Biotechnology, Graduate School of Natural Science and Technology, Okayama University, 3.1.1 Tsushima-Naka, Kita-ku, Okayama 700-8530, Japan.
2. Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, No. 156, Sanmalu, Nankai District, Tianjin, 300100, China.
3. Lurie Children's Research Center, Feinberg School of Medicine, Northwestern University, 2300 Children's Plaza, Box 222, Chicago, IL 60614-3394, USA.
4. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 2702, USA.
5. State Key Laboratory of Breast Cancer Research, Department of Breast Cancer Pathology and Research Laboratory, Cancer Hospital of Tianjin Medical University, Tianjin, China.


Several studies have shown that cancer niche can perform an active role in the regulation of tumor cell maintenance and progression through extracellular vesicles-based intercellular communication. However, it has not been reported whether this vesicle-mediated communication affects the malignant transformation of normal stem cells/progenitors. We have previously reported that the conditioned medium derived from the mouse Lewis Lung Carcinoma (LLC) cell line can convert mouse induced pluripotent stem cells (miPSCs) into cancer stem cells (CSCs), indicating that normal stem cells when placed in an aberrant microenvironment can give rise to functionally active CSCs. Here, we focused on the contribution of tumor-derived extracellular vesicles (tEVs) that are secreted from LLC cells to induce the transformation of miPSCs into CSCs. We isolated tEVs from the conditioned medium of LLC cells, and then the differentiating miPSCs were exposed to tEVs for 4 weeks. The resultant tEV treated cells (miPS-LLCev) expressed Nanog and Oct3/4 proteins comparable to miPSCs. The frequency of sphere formation of the miPS-LLCev cells in suspension culture indicated that the self-renewal capacity of the miPS-LLCev cells was significant. When the miPS-LLCev cells were subcutaneously transplanted into Balb/c nude mice, malignant liposarcomas with extensive angiogenesis developed. miPS-LLCevPT and miPS-LLCevDT, the cells established from primary site and disseminated liposarcomas, respectively, showed their capacities to self-renew and differentiate into adipocytes and endothelial cells. Moreover, we confirmed the secondary liposarcoma development when these cells were transplanted. Taken together, these results indicate that miPS-LLCev cells possess CSC properties. Thus, our current study provides the first evidence that tEVs have the potential to induce CSC properties in normal tissue stem cells/progenitors.

Keywords: cancer stem cells, mouse induced pluripotent stem cells, extracellular vesicles, cancerous niche, liposarcoma.

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How to cite this article:
Yan T, Mizutani A, Chen L, Takaki M, Hiramoto Y, Matsuda S, Shigehiro T, Kasai T, Kudoh T, Murakami H, Masuda J, Hendrix MJC, Strizzi L, Salomon DS, Fu L, Seno M. Characterization of Cancer Stem-Like Cells Derived from Mouse Induced Pluripotent Stem Cells Transformed by Tumor-Derived Extracellular Vesicles. J Cancer 2014; 5(7):572-584. doi:10.7150/jca.8865. Available from http://www.jcancer.org/v05p0572.htm