論文

査読有り 国際誌
2020年5月1日

Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state.

International journal of cancer
  • Kosuke Mizukoshi
  • ,
  • Yu Okazawa
  • ,
  • Hiroshi Haeno
  • ,
  • Yu Koyama
  • ,
  • Kaidiliayi Sulidan
  • ,
  • Hiromitsu Komiyama
  • ,
  • Harumi Saeki
  • ,
  • Naomi Ohtsuji
  • ,
  • Yasuhiko Ito
  • ,
  • Yutaka Kojima
  • ,
  • Michitoshi Goto
  • ,
  • Sonoko Habu
  • ,
  • Okio Hino
  • ,
  • Kazuhiro Sakamoto
  • ,
  • Akira Orimo

146
9
開始ページ
2547
終了ページ
2562
記述言語
英語
掲載種別
DOI
10.1002/ijc.32672

Emerging evidence supports the theory that tumor cell clusters efficiently metastasize to distant organs. However, the roles of epithelial-to-mesenchymal transition (EMT) in metastasizing tumor cell clusters have not yet been fully elucidated. To investigate this issue, tumor fragments were dissected from 40 colorectal cancer (CRC) patients and implanted subcutaneously into immunodeficient mice. We observed that tumors developed from the tumor fragments obtained from 28 of the 40 CRC patients. The tumors were then dissociated into cell suspensions to be orthotopically injected into secondary mice. The tumors from 13 of the 28 patients progressed. Furthermore, metastases formed spontaneously in the liver and lungs from the tumor fragments obtained from 8 of these 13 patients. Moreover, employing a mathematical analysis, we showed that tumor cell clusters seeded these metastases significantly more often than did single tumor cells. Membrane E-cadherin- and nuclear ZEB1-positive tumor cells indicating the hybrid epithelial/mesenchymal state were also detected in primary tumors of various CRC patients, and in the corresponding patient-derived xenografts (PDXs) and circulating tumor cell clusters in the bloodstreams of mice. In contrast, ZEB1 staining was barely detectable in the patient-matched liver metastases presumably developing through mesenchymal-to-epithelial transition. Inhibition of E-cadherin or ZEB1 expression by shRNA notably prevented the PDX-derived tumor organoids from colonizing the liver, when injected intrasplenically into mice, indicating E-cadherin and ZEB1 expressions to be required for their metastatic colonization. Taken together, these findings suggest that the epithelial/mesenchymal state mediates metastatic seeding of human CRC cell clusters into distant organs.

リンク情報
DOI
https://doi.org/10.1002/ijc.32672
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/31506938

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