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January 05, 2017

The organ determines if a gene is cancerous

Researchers at CiRA demonstrate that the malignancy of an oncogene varies with the organ

Oncogenes are genes in which mutations are associated with cancer. Hundreds of oncogenes exist, but in most cases, how they initiate the cancer is poorly understood.

"Mutations in the Apc gene are interesting, because they cause cancer only in the intestine even though they are found throughout the body," said CiRA Professor and Pathologist Yasuhiro Yamada.

To understand why, Yamada and his team of researchers used iPS cell technology to reprogram cancer cells caused by the Apc gene. "Reprogrammed tumor cells (RTCs) are like iPS cells but have some important differences," he noted.

One difference is pluripotency. By definition, pluripotency gives a cell the ability to be differentiated into any cell type equally, but RTCs were biased to form placental cells.

"We attributed this to the Apc mutation," said Kyoichi Hashimoto, one of the lead authors of the new study, which can be read in PNAS. "We therefore rescued the mutation and looked at the effects in mice."

Indeed, rescuing the gene resulted in RTCs that were pluripotent and had a gene expression profile that was consistent of ES cells. At the same time, forcing the Apc mutation in ES cells compromised pluripotency and converted the gene expression profile to one akin of RTCs.

When injected into mice, the rescued RTCs contributed to producing all the organs in the body. With the Apc gene rescued, no tumors were found. On the other hand, when the gene was disrupted in fully developed mice, tumors formed, but only in intestine, suggesting that something in the intestine itself triggered the malignancy.

"Our results suggest that genetic changes are not enough to cause the cancer in intestine," said Yamada. Indeed, additional study showed that the intestinal tumors showed a pattern of methylation changes that was absent in both RTCs and rescued RTCs. "Controlling these epigenetic changes may control the cancer," Yamada remarked.

Paper Details
  • Journal: Proceedings of the National Academy of Sciences
  • Title: The cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior
  • Authors: Kyoichi Hashimoto1,2,*, Yosuke Yamada1,3,*, Katsunori Semi1,4, Masaki Yagi1, Akito Tanaka1, Fumiaki Itakura1, Hitomi Aoki5, Takahiro Kunisada5, Knut Woltjen1,6, Hironori Haga3, Yoshiharu Sakai2, Takuya Yamamoto1,4,7, and Yasuhiro Yamada1,4

    * co-first author
  • Author Affiliations:
    1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    2. Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
    3. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
    4. Institute for Integrated Cell-Material Sciences (WPI-iCeMS), Kyoto University, Kyoto, Japan
    5. Graduate School of Medicine, Gifu University Gifu, Japan
    6. Hakubi Center for Advanced Research, Kyoto, Japan
    7. AMED-CREST, Tokyo, Japan
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