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Short-Term Circulating Tumor Cell Dynamics in Mouse Xenograft Models and Implications for Liquid Biopsy.

ABSTRACT: Motivation:Circulating tumor cells (CTCs) are widely studied using liquid biopsy methods that analyze fractionally-small peripheral blood (PB) samples. However, little is known about natural fluctuations in CTC numbers that may occur over short timescales in vivo, and how these may affect detection and enumeration of rare CTCs from small blood samples. Methods:We recently developed an optical instrument called "diffuse in vivo flow cytometry" (DiFC) that uniquely allows continuous, non-invasive counting of rare, green fluorescent protein expressing CTCs in large blood vessels in mice. Here, we used DiFC to study short-term changes in CTC numbers in multiple myeloma and Lewis lung carcinoma xenograft models. We analyzed CTC detections in over 100 h of DiFC data, and considered intervals corresponding to approximately 1%, 5%, 10%, and 20% of the PB volume. In addition, we analyzed changes in CTC numbers over 24 h (diurnal) periods. Results:For rare CTCs (fewer than 1 CTC per ml of blood), the use of short DiFC intervals (corresponding to small PB samples) frequently resulted in no detections. For more abundant CTCs, CTC numbers frequently varied by an order of magnitude or more over the time-scales considered. This variance in CTC detections far exceeded that expected by Poisson statistics or by instrument variability. Rather, the data were consistent with significant changes in mean numbers of CTCs on the timescales of minutes and hours. Conclusions:The observed temporal changes can be explained by known properties of CTCs, namely, the continuous shedding of CTCs from tumors and the short half-life of CTCs in blood. It follows that the number of cells in a blood sample are strongly impacted by the timing of the draw. The issue is likely to be compounded for multicellular CTC clusters or specific CTC subtypes, which are even more rare than single CTCs. However, we show that enumeration can in principle be improved by averaging multiple samples, analysis of larger volumes, or development of methods for enumeration of CTCs directly in vivo.

SUBMITTER: Williams AL

PROVIDER: S-EPMC7677561 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Short-Term Circulating Tumor Cell Dynamics in Mouse Xenograft Models and Implications for Liquid Biopsy.

Williams Amber L AL Fitzgerald Jessica E JE Ivich Fernando F Sontag Eduardo D ED Niedre Mark M

Frontiers in oncology 20201106

<h4>Motivation</h4>Circulating tumor cells (CTCs) are widely studied using liquid biopsy methods that analyze fractionally-small peripheral blood (PB) samples. However, little is known about natural fluctuations in CTC numbers that may occur over short timescales <i>in vivo</i>, and how these may affect detection and enumeration of rare CTCs from small blood samples.<h4>Methods</h4>We recently developed an optical instrument called "diffuse <i>in vivo</i> flow cytometry" (DiFC) that uniquely all ...[more]

PMID: 33240820

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Project description:Background/objectivesNon-alcoholic fatty liver disease (NAFLD) causes a wide spectrum of liver damage, from simple steatosis (SS) to cirrhosis. SS and non-alcoholic steatohepatitis (NASH) cannot be distinguished by clinical or laboratory features. Dysregulation of the gut microbiota is involved in NASH pathogenesis. The aim of this study was to assess the relationship between microbiota-derived metabolites and the degrees of NAFLD; also, to investigate whether these metabolites could be included in a panel of NASH biomarkers.Subjects/methodsWe used liquid chromatography coupled to triple-quadrupole-mass spectrometry (LC-QqQ) analysis to quantify choline and its derivatives, betaine, endogenous ethanol, bile acids, short-chain fatty acids and soluble TLR4 in serum from women with normal weight (n = 29) and women with morbid obesity (MO) (n = 82) with or without NAFLD. We used real-time polymerase chain reaction (RT-PCR) analysis to evaluate the hepatic and intestinal expression level of all genes studied (TLR2, TLR4, TLR9, LXRα, SREBP1C, ACC1, FAS, PPARα, CPT1α, CROT, SREBP2, ABCA1, ABCG1 and FXR in the liver; TLR2, TLR4, TLR5, TLR9, GLP-1R, DPP-4, FXR and PPARɣ in the jejunum) in 82 women with MO with normal liver histology (NL, n = 29), SS (n = 32), and NASH (n = 21).ResultsHepatic FAS, TLR2, and TLR4 expression were overexpressed in NAFLD patients. TLR2 was overexpressed in NASH patients. In women with MO with NAFLD, we found upregulation of intestinal TLR9 expression and downregulation of intestinal FXR expression in women with NASH. Circulating TMAO, glycocholic acid and deoxycholic acid levels were significantly increased in NAFLD patients. Endogenous circulating ethanol levels were increased in NASH patients in comparison to those in SS patients.ConclusionsThese findings suggest that the intestine participates in the progression of NAFLD. Moreover, levels of certain circulating microbiota-related metabolites are associated with NAFLD severity and could be used as a "liquid biopsy" in the noninvasive diagnosis of NASH.

Dataset Information

Short-Term Circulating Tumor Cell Dynamics in Mouse Xenograft Models and Implications for Liquid Biopsy.

Publications

Short-Term Circulating Tumor Cell Dynamics in Mouse Xenograft Models and Implications for Liquid Biopsy.

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