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Parp-1 deficiency in ES cells promotes invasive and metastatic lesions accompanying induction of trophoblast giant cells during tumorigenesis in uterine environment

Authors

  • Tadashige Nozaki,

    1. Division of Biochemistry, National Cancer Center Research Institute, Tokyo, Japan
    2. Department of Pharmacology, Osaka Dental University, Osaka, Japan
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  • Hiroaki Fujimori,

    1. Division of Biochemistry, National Cancer Center Research Institute, Tokyo, Japan
    2. Division of Genome Stability Research, National Cancer Center Research Institute, Tokyo, Japan
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  • Junhui Wang,

    1. Division of Genome Stability Research, National Cancer Center Research Institute, Tokyo, Japan
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  • Hiroshi Suzuki,

    1. Research Unit for Functional Genomics, National Research Center for Protozoan Diseases, Obihiro University of Agriculture and Veterinary Medicine, Obihiro, Japan
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  • Hiroshi Imai,

    1. Pathology Division, Mie University Hospital, Mie, Japan
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  • Masatoshi Watanabe,

    1. Laboratory for Medical Engineering, Division of Materials Science and Chemical Engineering, Graduate School of Engineering, Yokohama National University, Yokohama, Japan
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  • Kiyoshi Ohura,

    1. Department of Pharmacology, Osaka Dental University, Osaka, Japan
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  • Mitsuko Masutani

    Corresponding author
    1. Division of Genome Stability Research, National Cancer Center Research Institute, Tokyo, Japan
    2. ADP-Ribosylation in Oncology Project, National Cancer Center Research Institute, Tokyo, Japan
    • Division of Biochemistry, National Cancer Center Research Institute, Tokyo, Japan
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Correspondence: Mitsuko Masutani, PhD, Division of Genome Stability Research, National Cancer Center Research Institute, 1-1 Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. Email: mmasutan@ncc.go.jp

Abstract

Embryonic stem (ES) cells deficient in poly(ADP-ribose) polymerase-1 (Parp-1) develop into teratocarcinomas with the appearance of trophoblast giant cells (TGCs) when injected subcutaneously into nude mice. Because the uterus is one of the original organs in which germ cell tumors develop with induction of trophoblast lineage, here we investigated whether Parp-1 deficiency in ES cells affects teratocarcinoma formation processes by grafting ES cells into the horns of uteri. Teratocarcinomas developed from both wild-type (Parp-1+/+) and Parp-1−/− ES cells. The weights of the tumors derived from Parp-1−/− ES cells were lower than those of the tumors derived from Parp-1+/+ ES cells (P < 0.05). The Parp-1−/− tumors showed the appearance of TGCs. Notably, organ metastasis to the lung and liver was observed for the Parp-1−/− tumors, but not for the Parp-1+/+ tumors (P < 0.05). Invasions were more frequently observed with the Parp-1−/− tumors compared with the Parp-1+/+ tumors (P < 0.05). Since TGCs are known to have invasive properties, the appearance of TGCs may have supported the metastatic process. The present findings suggest that loss of Parp-1 during teratocarcinoma formation might augment invasive and metastatic properties of the tumors in the uterine environment.

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