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

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.

Impact of Circadian Rhythms on the Development and Clinical Management of Genitourinary Cancers

“…Advanced GU cancers have poor outcomes and high mortality rates, making the development of therapeutic targets a time-sensitive task ( 142 ). A pioneering research study of circulating tumor cells, which are biomarkers of metastasis, has shown to follow specific circadian rhythmicity in animal models of PCa ( 143 ). By targeting PCa treatment to coincide when circulating tumor cells are at their highest concentration in the bloodstream, clinicians may be able to produce robust patient responses to treatment ( 143 ).…”

A Narrow Straight Microchannel Array for Analysis of Transiting Speed of Floating Cancer Cells

“…In fact, the analytical model developed in this work can be further applied to predict the cell transiting speed for other cell types with different ranges of physical parameters (e.g., diameter and elasticity) and microchannel configurations (e.g., width and height); and therefore this model can guide the design of microchannels for a specific cell type flowing within a target range of the transiting speed for any further biosensing applications, including viscoelasticity measurements [32] and characterization of fluorescence signals from the in vivo flow cytometry [33] for CTCs.…”

Chronoradiobiology of Breast Cancer: The Time Is Now to Link Circadian Rhythm and Radiation Biology

“…Indeed, one might expect tumors to desynchronize from an individual's circadian rhythm, considering that malignant cells often have dysfunctional clock gene expressions. A recent prostate cancer model demonstrated tumor behavior that was in phase with the circadian rhythm of host mice, but desynchronization into non-24-h rhythms has been documented in a variety of human cancers [155,156]. Future research might consider to what extent tumors resynchronize in response to host entrainment.…”