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Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state
Author(s) -
Mizukoshi Kosuke,
Okazawa Yu,
Haeno Hiroshi,
Koyama Yu,
Sulidan Kaidiliayi,
Komiyama Hiromitsu,
Saeki Harumi,
Ohtsuji Naomi,
Ito Yasuhiko,
Kojima Yutaka,
Goto Michitoshi,
Habu Sonoko,
Hino Okio,
Sakamoto Kazuhiro,
Orimo Akira
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32672
Subject(s) - mesenchymal stem cell , seeding , colorectal cancer , cancer research , metastasis , cell , pathology , epithelial–mesenchymal transition , biology , cancer , medicine , biochemistry , genetics , agronomy
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.