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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2020

Open Access 01-12-2020 | Metastasis | Research

Metabolic classification of circulating tumor cells as a biomarker for metastasis and prognosis in breast cancer

Authors: Jing Chen, Changsheng Ye, Jianyu Dong, Shunwang Cao, Yanwei Hu, Bo Situ, Xiaoxue Xi, Sihua Qin, Jiasen Xu, Zhen Cai, Lei Zheng, Qian Wang

Published in: Journal of Translational Medicine | Issue 1/2020

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Abstract

Background

Circulating tumor cells (CTCs) has been demonstrated as a promising liquid biopsy marker for breast cancer (BC). However, the intra-patient heterogeneity of CTCs remains a challenge to clinical application. We aim at profiling aggressive CTCs subpopulation in BC utilizing the distinctive metabolic reprogramming which is a hallmark of metastatic tumor cells.

Methods

Oncomine, TCGA and Kaplan–Meier plotter databases were utilized to analyze expression and survival relevance of the previously screened metastasis-promoting metabolic markers (PGK1/G6PD) in BC patients. CTCs detection and metabolic classification were performed through micro-filtration and multiple RNA in situ hybridization using CD45 and PGK1/G6PD probes. Blood samples were collected from 64 BC patients before treatment for CTCs analysis. Patient characteristics were recorded to evaluate clinical applications of CTCs metabolic subtypes, as well as morphological EMT subtypes classified by epithelial (EpCAM/CKs) and mesenchymal (Vimentin/Twist) markers.

Results

PGK1 and G6PD expressions were up-regulated in invasive BC tissues compared with normal mammary tissues. Increased tissue expressions of PGK1 or G6PD indicated shortened overall and relapse-free survival of BC patients (P < 0.001). Blood GM+CTCs (DAPI+CD45−PGK1/G6PD+) was detectable (range 0–54 cells/5 mL) in 61.8% of tCTCs > 0 patients. Increased GM+CTCs number and positive rate were correlated with tumor metastasis and progression (P < 0.05). The GM+CTCs ≥ 2/5 mL level presented superior AUC of ROC at 0.854 (95% CI 0.741–0.968) in the diagnosis of BC metastasis (sensitivity/specificity: 66.7%/91.3%), compared with that of tCTCs (0.779) and CTCs-EMT subtypes (E-CTCs 0.645, H-CTCs 0.727 and M-CTCs 0.697). Moreover, GM+CTCs+ group had inferior survival with decreased 2 years-PFS proportion (18.5%) than GM+CTCs− group (87.9%; P = 0.001).

Conclusions

This work establishes a PGK1/G6PD-based method for CTCs metabolic classification to identify the aggressive CTCs subpopulation. Metabolically active GM+CTCs subtype is suggested a favorable biomarker of distant metastasis and prognosis in BC patients.
Appendix
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Metadata
Title
Metabolic classification of circulating tumor cells as a biomarker for metastasis and prognosis in breast cancer
Authors
Jing Chen
Changsheng Ye
Jianyu Dong
Shunwang Cao
Yanwei Hu
Bo Situ
Xiaoxue Xi
Sihua Qin
Jiasen Xu
Zhen Cai
Lei Zheng
Qian Wang
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2020
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-020-02237-8

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