Cancer Letters

Cancer Letters

Volume 412, 1 January 2018, Pages 99-107
Cancer Letters

Original Article
Quantified postsurgical small cell size CTCs and EpCAM+ circulating tumor stem cells with cytogenetic abnormalities in hepatocellular carcinoma patients determine cancer relapse

https://doi.org/10.1016/j.canlet.2017.10.004Get rights and content
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Highlights

  • SE-iFISH was improved to effectively detect and comprehensively characterize diverse subtypes of CC and HCC CTCs.

  • Existence of small aneuploid HCC CTCs (≤WBCs), and correlation of those small CTCs to clinical outcomes were demonstrated.

  • Postsurgical quantity of EpCAM+ CTSCs, triploid EpCAM small CTCs and CTMs, highly correlated to HCC recurrence.

Abstract

Detection of hepatocellular carcinoma circulating tumor cells performed with conventional strategies, is significantly limited due to inherently heterogeneous and dynamic expression of EpCAM, as well as degradation of cytokeratins during epithelial-to-mesenchymal transition, which inevitably lead to non-negligible false negative detection of such “uncapturable and invisible” CTCs. A novel SE-iFISH strategy, improved for detection of HCC CTCs in this study, was applied to comprehensively detect, in situ phenotypically and karyotypically characterize hepatocellular and cholangiocarcinoma CTCs (CD45/CD31) in patients subjected to surgical resection. Clinical significance of diverse subtypes of CTC was systematically investigated. Existence of small cell size CTCs (≤5 μm of WBCs) with cytogenetic abnormality of aneuploid chromosome 8, which constituted majority of the detected CTCs in HCC patients, was demonstrated for the first time. The stemness marker EpCAM+ aneuploid circulating tumor stem cells (CTSCs), and EpCAM small CTCs with trisomy 8, promote tumor growth. Postsurgical quantity of small triploid CTCs (≥5 cells/6 ml blood), multiploid (≥pentasomy 8) CTSCs or CTM (either one ≥ 1) significantly correlated to HCC patients' poor prognosis, indicating that detection of those specific subtypes of CTCs and CTSCs in post-operative patients help predict neoplasm recurrence.

Keywords

iFISH
Aneuploid CTC and circulating tumor stem cell
Hepatobiliary malignancy
Hepatocellular and cholangiocarcinoma
Surgical resection

Abbreviations

HCC
hepatocellular carcinoma
CC
cholangiocarcinoma
CTC
circulating tumor cell
CTSC
circulating tumor stem cell
DTC
disseminated tumor cell
CTM
circulating tumor microemboli
EC
endothelial cell
CEC
circulating endothelial cell
nCAC
non-hematopoietic circulating aneuploid cell
EMT
epithelial-to-mesenchymal transition
CK
cytokeratin
SE
subtraction enrichment
iFISH
immunostaining-fluorescence in situ hybridization
DFS
disease-free survival

Cited by (0)

1

Co-first authors.