Plastin3 Is a Novel Marker for Circulating Tumor Cells Undergoing the Epithelial–Mesenchymal Transition and Is Associated with Colorectal Cancer Prognosis

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 ¼ 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 EMTinduced 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 ¼ 381) and the validation set [n ¼ 330; HR ¼ 2.17; 95% confidence interval (CI) ¼ 1.38-3.40 and HR ¼ 3.92; 95% CI ¼ 2.27-6.85]. The association between PLS3-positive CTC and prognosis was particularly strong in patients with Dukes B (HR ¼ 4.07; 95% CI ¼ 1.50-11.57) and Dukes C (HR ¼ 2.57; 95% CI ¼ 1.42-4.63). PLS3 is a novel marker for metastatic CRC cells, and it possesses significant prognostic value. Cancer Res; 73(7); 2059-69. Ó2012 AACR.

Circulating Tumor Cells: A Review of Non–EpCAM-Based Approaches for Cell Enrichment and Isolation

“…Yokobori et al described plastin 3 as a good alternative for avoiding the use of large cocktails of antibodies, because this marker is not downregulated in CTCs during their EMT and is not expressed in blood cells (73 ). Although positive selection is very specific and a high purity can be obtained, the presence of some uncharacterized CTCs in each individual blood sample should be taken into consideration.…”

Clinical studies monitoring circulating and disseminated tumor cells in gastrointestinal cancers

“…Plastin3 positivity in the PB was found to be associated with clinicopathological risk factors, such as depth of invasion, lymph node and liver metastasis, presence of peritoneal dissemination, increased recurrence rate, and higher Dukes stage. It is very important to note that plastin3 expression was also detected in all patients with recurrent disease, and at a level higher than in the case of prerecurrence and of patients without recurrence [34]. The correlation between CTCs and prognosis in CRCs was stronger if CKs and multiple markers were used than for the one-marker assay [35].…”

Detection and Clinical Significance of Circulating Tumor Cells in Colorectal Cancer—20 Years of Progress

“…Dukes B subset (54). Taken together, these findings suggest that OLFM4, LGR5 and PLS3 may be useful to include in marker panels for the detection of CTSCs.…”