Cancer Stem Cells derived from mouse iPS cells (PASRM 2013-001)

The cancer stem cells (CSCs) capable of continuous proliferation and self-renewal are considered to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. CSCs should be derived from normal stem cells affected by the tumor microenvironment although the mechanism of development is not clear yet. On the other hand, induced pluripotent stem cells (iPSCs) as well as embryonic stem cells are considered to be induced into progenitor cells, which differentiate into various normal phenotypes depending on the normal niche. We hypothesized that CSCs could be derived from iPSCs in the conditioned culture medium of cancer cell lines, which might be a mimic of carcinoma microenvironment. In this study, we employed Nanog mouse iPSCs, in which GFP gene has been inserted into the 5' untranslated region of the Nanog gene. As a result, the cells treated with the conditioned medium for 4 weeks exhibited a high tumorigenicity in vivo with a capacity of self-renewal and the expression of markers associated with stem cell properties and an undifferentiated state. The cells efficiently formed spheroids expressing GFP in suspension culture, vasculogenic tubes in the presence of type IV collagen in vitro and exhibited extensive angiogenesis in vivo, which was confirmed by magnetic resonance imaging and by histochemical analysis. From the tumors the CSCs expressing GFP were isolated as spheroid forming cells in the primary culture. These cells showed almost the same characters as those found in the originally transplanted CSCs. Furthermore, the CSCs exhibited extensive metastasis to lung when injected into tail vein. Thus we concluded that a model of CSCs was originally developed using mouse iPSCs and proposed the conditioned culture medium might perform as niche for producing CSCs. It is worthwhile noticing that the mouse iPSCs co-cultured with cancer-derived cells did not form malignant tumors in vivo. This implies that cell-to-cell contact may have inhibitory effect on the conversion of mouse iPSCs into CSCs. The tumor microenvironment, which converted mouse iPSCs to CSCs, as well as the heterogeneity in tumor tissues will be further discussed