Terasawa H, Kinugasa H, Nouso K, Yamamoto S, Hirai M, Tanaka T, Takaki A, Okada H. Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma. World J Gastroenterol 2021; 27(41): 7134-7143 [PMID: 34887633 DOI: 10.3748/wjg.v27.i41.7134]
Corresponding Author of This Article
Hideaki Kinugasa, MD, PhD, Doctor, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho Kita-Ku, Okayama 7008558, Japan. gyacy14@gmail.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
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Terasawa H, Kinugasa H, Nouso K, Yamamoto S, Hirai M, Tanaka T, Takaki A, Okada H. Circulating tumor DNA dynamics analysis in a xenograft mouse model with esophageal squamous cell carcinoma. World J Gastroenterol 2021; 27(41): 7134-7143 [PMID: 34887633 DOI: 10.3748/wjg.v27.i41.7134]
Hiroyuki Terasawa, Hideaki Kinugasa, Kazuhiro Nouso, Shumpei Yamamoto, Mami Hirai, Akinobu Takaki, Hiroyuki Okada, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 7008558, Japan
Takehiro Tanaka, Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 7008558, Japan
Author contributions: Kinugasa H designed the manuscript; Terasawa H drafted the manuscript; Kinugasa H, Terasawa H, Yamamoto S, Hirai M, Tanaka T and Takaki A were responsible for experiments; Kinugasa H, Nouso K and Okada H supervised the manuscript preparation; all authors approved the final manuscript.
Supported byJSPS KAKENHI (19k17433).
Institutional review board statement: This study was reviewed approved by [the ethics committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Okayama University Hospital] Institutional Review Board.
Institutional animal care and use committee statement: Xenograft mouse experimental protocols were approved by the Ethical Committee of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (OKU-2019276).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Hideaki Kinugasa, MD, PhD, Doctor, Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-Cho Kita-Ku, Okayama 7008558, Japan. gyacy14@gmail.com
Received: May 14, 2021 Peer-review started: May 14, 2021 First decision: July 14, 2021 Revised: July 21, 2021 Accepted: August 30, 2021 Article in press: August 30, 2021 Published online: November 7, 2021 Processing time: 175 Days and 20.5 Hours
Abstract
BACKGROUND
It remains unclear which factors, such as tumor volume and tumor invasion, influence circulating tumor DNA (ctDNA), and the origin of ctDNA in liquid biopsy is always problematic. To use liquid biopsies clinically, it will be very important to address these questions.
AIM
To assess the origin of ctDNA, clarify the dynamics of ctDNA levels, assess ctDNA levels by using a xenograft mouse after treatment, and to determine whether tumor volume and invasion are related to ctDNA levels.
METHODS
Tumor xenotransplants were established by inoculating BALB/c-nu/nu mice with the TE11 cell line. Groups of mice were injected with xenografts at two or four sites and sacrificed at the appropriate time point after xenotransplantation for ctDNA analysis. Analysis of ctDNA was performed by droplet digital PCR, using the human telomerase reverse transcriptase (hTERT) gene.
RESULTS
Mice given two-site xenografts were sacrificed for ctDNA at week 4 and week 8. No hTERT was detected at week 4, but it was detected at week 8. However, in four-site xenograft mice, hTERT was detected both at week 4 and week 6. These experiments revealed that both tumor invasion and tumor volume were associated with the detection of ctDNA. In resection experiments, hTERT was detected at resection, but had decreased by 6 h, and was no longer detected 1 and 3 d after resection.
CONCLUSION
We clarified the origin and dynamics of ctDNA, showing that tumor volume is an important factor. We also found that when the tumor was completely resected, ctDNA was absent after one or more days.
Core Tip: We clarified the origin and dynamics of circulating tumor DNA (ctDNA), showing that not only tumor invasion but also tumor volume was an important factor. The possibility of detecting ctDNA in early-stage cancers with shallow depth was demonstrated. Also, ctDNA could be measured at 1 d after tumor resection to evaluate the residuals, and the half-life of ctDNA was estimated to be 1.8-3.2 h.
