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. 2019 Sep 5;10:3999. doi: 10.1038/s41467-019-11745-1

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© The Author(s) 2019

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — One-step secondary sarcoma development in sarcoma-induced pluripotent stem cells (iPSC) mice. a iPSC-like cells were generated from a murine clear-cell sarcoma (CCS) cell line (G1297) by introducing four reprogramming factors. Scale bars: 600 µm (upper), 300 µm (lower). b Array comparative genomic hybridization (CGH) analysis reveals that sarcoma-derived iPSC-like cells (clone G3) share identical chromosomal aberrations with parental sarcoma cells (G1297). c Candidate mutation sites in sarcoma cells (G1297) and sarcoma-derived iPSC-like cells (clone G3). Exome analysis reveals that more than 75% of candidate mutation sites in G1297 are overlapped with those in sarcoma-derived iPSC-like cells. d Sarcoma-derived iPSC-like cells contributed to adult chimeric mice after injection into blastocyst. e Secondary sarcoma development in sarcoma-iPSC mice treated with doxycycline (Dox). Secondary sarcoma preferentially arose in soft tissue. Left, center of chest and abdominal wall (Dox 1 week). Middle, subcutaneous tissue; right, abdominal fascia (Dox 4–5 weeks). f Secondary sarcoma developed at the subcutaneous layer (left) in sarcoma-iPSC mouse. Both iPSC G1- and G3-derived mice developed subcutaneous tumors. Histological analysis reveals that secondary sarcomas resemble primary CCS. EWS/ATF1 expression is detectable in secondary tumors by immunohistochemistry using hemagglutinin (HA) antibody. Scale bars: 100 µm. g Histology and Ki67-positive cell ratio of primary CCSs and secondary sarcomas. Scale bars: 50 µm. Primary CCSs were obtained from EWS/ATF1-induced embryonic stem cell (ESC) mice (Rosa-M2rtTA/Col1a1::tetO-EWS/ATF1-ires-mCherry), while secondary sarcomas were obtained from sarcoma-iPSC mice, which were generated with two independent iPSC clones (G1 and G3). The mean ± SD of six independent primary and secondary sarcomas are shown, respectively. No significant difference in the Ki67-positive cell ratio is observed between them (P = 0.4438, two-sided Student’s t test). h Tumor incidence within 2 weeks after Dox administration in chimeric mice generated with control ESCs, ETF-iPSCs (ear-tip fibroblast-iPSCs), and sarcoma-iPSCs. Sarcoma-iPSC mice developed secondary sarcomas at a higher incidence and shorter latency than other mice. Pink bar shows the incidence of macroscopic sarcoma, and blue bar shows the incidence of microscopic sarcoma. i iPSC derivation from an independent sarcoma cell line (K11). A higher incidence and shorter latency of secondary sarcoma development were observed in sarcoma (K11)-iPSC mice within 2 weeks. Scale bars: 600 µm (left upper), 300 µm (left lower), 200 µm (right upper), and 50 µm (right lower)