Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis

Takehiko Yokobori, Hisae Iinuma, Teppei Shimamura, Seiya Imoto, Keishi Sugimachi, Hideshi Ishii, Masaaki Iwatsuki, Daisuke Ota, Masahisa Ohkuma, Takeshi Iwaya, Naohiro Nishida, Ryunosuke Kogo, Tomoya Sudo, Fumiaki Tanaka, Kohei Shibata, Hiroyuki Toh, Tetsuya Sato, Graham F. Barnard, Takeo Fukagawa, Seiichiro YamamotoHayao Nakanishi, Shin Sasaki, Satoru Miyano, Toshiaki Watanabe, Hiroyuki Kuwano, Koshi Mimori, Klaus Pantel, Masaki Mori

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Abstract

Circulating tumor cells (CTC) in blood have attracted attention both as potential seeds for metastasis and as biomarkers. However, most CTC detection systems might miss epithelial-mesenchymal transition (EMT)-induced metastatic cells because detection is based on epithelial markers. First, to discover novel markers capable of detecting CTCs in which EMT has not been repressed, microarray analysis of 132 colorectal cancers (CRC) from Japanese patients was conducted, and 2,969 genes were detected that were overexpressed relative to normal colon mucosa. From the detected genes, we selected those that were overexpressed CRC with distant metastasis. Then, we analyzed the CRC metastasis-specific genes (n = 22) to determine whether they were expressed in normal circulation. As a result, PLS3 was discovered as a CTC marker that was expressed in metastatic CRC cells but not in normal circulation. Using fluorescent immunocytochemistry, we validated that PLS3 was expressed in EMT-induced CTC in peripheral blood from patients with CRC with distant metastasis. PLS3-expressing cells were detected in the peripheral blood of approximately one-third of an independent set of 711 Japanese patients with CRC. Multivariate analysis showed that PLS3-positive CTC was independently associated with prognosis in the training set (n = 381) and the validation set [n = 330; HR = 2.17; 95% confidence interval (CI) = 1.38-3.40 and HR = 3.92; 95% CI = 2.27-6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR = 4.07; 95% CI = 1.50-11.57) and Dukes C (HR = 2.57; 95% CI = 1.42-4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value.

Original languageEnglish
Pages (from-to)2059-2069
Number of pages11
JournalCancer Research
Volume73
Issue number7
DOIs
Publication statusPublished - Apr 1 2013

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Yokobori, T., Iinuma, H., Shimamura, T., Imoto, S., Sugimachi, K., Ishii, H., Iwatsuki, M., Ota, D., Ohkuma, M., Iwaya, T., Nishida, N., Kogo, R., Sudo, T., Tanaka, F., Shibata, K., Toh, H., Sato, T., Barnard, G. F., Fukagawa, T., ... Mori, M. (2013). Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis. Cancer Research, 73(7), 2059-2069. https://doi.org/10.1158/0008-5472.CAN-12-0326