In vivo flow cytometry reveals a circadian rhythm of circulating tumor cells

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Abstract

Circulating tumor cells (CTCs) is an established biomarker of cancer metastasis. The circulation dynamics of CTCs are important for understanding the mechanisms underlying tumor cell dissemination. Although studies have revealed that the circadian rhythm may disrupt the growth of tumors, it is generally unclear whether the circadian rhythm controls the release of CTCs. In clinical examinations, the current in vitro methods for detecting CTCs in blood samples are based on a fundamental assumption that CTC counts in the peripheral blood do not change significantly over time, which is being challenged by recent studies. Since it is not practical to draw blood from patients repeatedly, a feasible strategy to investigate the circadian rhythm of CTCs is to monitor them by in vivo detection methods. Fluorescence in vivo flow cytometry (IVFC) is a powerful optical technique that is able to detect fluorescent circulating cells directly in living animals in a noninvasive manner over a long period of time. In this study, we applied fluorescence IVFC to monitor CTCs noninvasively in an orthotopic mouse model of human prostate cancer. We observed that CTCs exhibited stochastic bursts over cancer progression. The probability of the bursting activity was higher at early stages than at late stages. We longitudinally monitored CTCs over a 24-h period, and our results revealed striking daily oscillations in CTC counts that peaked at the onset of the night (active phase for rodents), suggesting that the release of CTCs might be regulated by the circadian rhythm.

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Most cited references 62

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Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases.

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Metastasis is the major cause of cancer-related deaths; therefore, the prevention and treatment of metastasis are fundamental to improving clinical outcomes. Epithelial mesenchymal transition (EMT), an evolutionarily conserved developmental program, has been implicated in carcinogenesis and confers metastatic properties upon cancer cells by enhancing mobility, invasion, and resistance to apoptotic stimuli. Furthermore, EMT-derived tumor cells acquire stem cell properties and exhibit marked therapeutic resistance. Given these attributes, the complex biological process of EMT has been heralded as a key hallmark of carcinogenesis, and targeting EMT pathways constitutes an attractive strategy for cancer treatment. However, demonstrating the necessity of EMT for metastasis in vivo has been technically challenging, and recent efforts to demonstrate a functional contribution of EMT to metastasis have yielded unexpected results. Therefore, determining the functional role of EMT in metastasis remains an area of active investigation. Studies using improved lineage tracing systems, dynamic in vivo imaging, and clinically relevant in vivo models have the potential to uncover the direct link between EMT and metastasis. This review focuses primarily on recent advances in and emerging concepts of the biology of EMT in metastasis in vivo and discusses future directions in the context of novel diagnostic and therapeutic opportunities.

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Massimo Cristofanilli, G Budd, Matthew Ellis … (2004)

We tested the hypothesis that the level of circulating tumor cells can predict survival in metastatic breast cancer. In a prospective, multicenter study, we tested 177 patients with measurable metastatic breast cancer for levels of circulating tumor cells both before the patients were to start a new line of treatment and at the first follow-up visit. The progression of the disease or the response to treatment was determined with the use of standard imaging studies at the participating centers. Outcomes were assessed according to levels of circulating tumor cells at baseline, before the patients started a new treatment for metastatic disease. Patients in a training set with levels of circulating tumor cells equal to or higher than 5 per 7.5 ml of whole blood, as compared with the group with fewer than 5 circulating tumor cells per 7.5 ml, had a shorter median progression-free survival (2.7 months vs. 7.0 months, P 18 months, P 18 months; P<0.001), and the reduced proportion of patients (from 49 percent to 30 percent) in the group with an unfavorable prognosis suggested that there was a benefit from therapy. The multivariate Cox proportional-hazards regression showed that, of all the variables in the statistical model, the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. The number of circulating tumor cells before treatment is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer. Copyright 2004 Massachusetts Medical Society

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Author and article information

Contributors

Yuanzhen Suo: suoyuanzhen@pku.edu.cn

Hao He:

ORCID: http://orcid.org/0000-0003-0832-8310

haohe@sjtu.edu.cn

Xunbin Wei: xwei01@sjtu.edu.cn

Journal

Journal ID (nlm-ta): Light Sci Appl

Journal ID (iso-abbrev): Light Sci Appl

Title: Light, Science & Applications

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-5545

ISSN (Electronic): 2047-7538

Publication date (Electronic): 28 May 2021

Publication date PMC-release: 28 May 2021

Publication date Collection: 2021

Volume: 10

Electronic Location Identifier: 110

Affiliations

[1 ]GRID grid.16821.3c, ISNI 0000 0004 0368 8293, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Med-X Research Institute and School of Biomedical Engineering, , Shanghai Jiao Tong University, ; 200030 Shanghai, China

[2 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Biomedical Pioneering Innovation Center, , Peking University, ; 100871 Beijing, China

[3 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, School of Life Sciences, , Peking University, ; 100871 Beijing, China

[4 ]GRID grid.443248.d, ISNI 0000 0004 0467 2584, School of Instrument Science and Optoelectronics Engineering, , Beijing Information Science and Technology University, ; 100192 Beijing, China

[5 ]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Biomedical Engineering Department, , Peking University, ; 100081 Beijing, China

[6 ]GRID grid.412474.0, ISNI 0000 0001 0027 0586, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), , Peking University Cancer Hospital and Institute, ; 100142 Beijing, China

Author information

Hao He http://orcid.org/0000-0003-0832-8310

Article

Publisher ID: 542

DOI: 10.1038/s41377-021-00542-5

PMC ID: 8160330

PubMed ID: 34045431

SO-VID: b56631f3-16d7-4fdf-8815-162c9cf8ce23

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 18 November 2020

Date revision received : 21 April 2021

Date accepted : 21 April 2021

Funding

Funded by: Special Fund for Research on National Major Research Instruments of China (Grant No. 62027824) National Key Research and Development Program of China (Grant No. 2019YFC1604604) National Science Fund for Distinguished Young Scholars (Grant No. 61425006) SJTU Medicine Engineering Interdisciplinary Research Fund (Grant No. YG2017MS19) Program of Shanghai Technology Research Leader (Grant No. 17XD1402200) Fundamental Research Funds for the Central Universities (Grant No. 81661168014) National Natural Science Foundation of China (Grant No. 61975118)

Funded by: National Natural Science Foundation of China (Grant No. 62075013)