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

TY - JOUR

T1 - Plastin3 is a novel marker for circulating tumor cells undergoing the epithelial-mesenchymal transition and is associated with colorectal cancer prognosis

AU - Yokobori, Takehiko

AU - Iinuma, Hisae

AU - Shimamura, Teppei

AU - Imoto, Seiya

AU - Sugimachi, Keishi

AU - Ishii, Hideshi

AU - Iwatsuki, Masaaki

AU - Ota, Daisuke

AU - Ohkuma, Masahisa

AU - Iwaya, Takeshi

AU - Nishida, Naohiro

AU - Kogo, Ryunosuke

AU - Sudo, Tomoya

AU - Tanaka, Fumiaki

AU - Shibata, Kohei

AU - Toh, Hiroyuki

AU - Sato, Tetsuya

AU - Barnard, Graham F

AU - Fukagawa, Takeo

AU - Yamamoto, Seiichiro

AU - Nakanishi, Hayao

AU - Sasaki, Shin

AU - Miyano, Satoru

AU - Watanabe, Toshiaki

AU - Kuwano, Hiroyuki

AU - Mimori, Koshi

AU - Pantel, Klaus

AU - Mori, Masaki

N1 - ©2012 AACR.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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.

AB - 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.

KW - Aged

KW - Apoptosis

KW - Blotting, Western

KW - Cell Proliferation

KW - Colorectal Neoplasms

KW - Epithelial-Mesenchymal Transition

KW - Female

KW - Humans

KW - Immunoenzyme Techniques

KW - Liver Neoplasms

KW - Lymphatic Metastasis

KW - Male

KW - Membrane Glycoproteins

KW - Microfilament Proteins

KW - Middle Aged

KW - Neoplasm Invasiveness

KW - Neoplasm Recurrence, Local

KW - Neoplasm Staging

KW - Neoplastic Cells, Circulating

KW - Prognosis

KW - RNA, Messenger

KW - Real-Time Polymerase Chain Reaction

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Tumor Markers, Biological

U2 - 10.1158/0008-5472.CAN-12-0326

DO - 10.1158/0008-5472.CAN-12-0326

M3 - SCORING: Journal article

C2 - 23378342

VL - 73

SP - 2059

EP - 2069

JO - CANCER RES

JF - CANCER RES

SN - 0008-5472

IS - 7

ER -