High blood flow shear stress values are associated with circulating tumor cells cluster disaggregation in a multi-channel microfluidic device.

Alessandra Marrella,Silvia Scaglione,Nicola Aceto,Giuseppe Firpo,Patrizia Guida,Gabriele Varani,Ivan Vaccari,Arianna Fedi,Marco Fato,Fang-Bao Tian

doi:10.1371/journal.pone.0245536

Abstract

Metastasis represents a dynamic succession of events involving tumor cells which disseminate through the organism via the bloodstream. Circulating tumor cells (CTCs) can flow the bloodstream as single cells or as multicellular aggregates (clusters), which present a different potential to metastasize. The effects of the bloodstream-related physical constraints, such as hemodynamic wall shear stress (WSS), on CTC clusters are still unclear. Therefore, we developed, upon theoretical and CFD modeling, a new multichannel microfluidic device able to simultaneously reproduce different WSS characterizing the human circulatory system, where to analyze the correlation between SS and CTC clusters behavior. Three physiological WSS levels (i.e. 2, 5, 20 dyn/cm2) were generated, reproducing values typical of capillaries, veins and arteries. As first validation, triple-negative breast cancer cells (MDA-MB-231) were injected as single CTCs showing that higher values of WSS are correlated with a decreased viability. Next, the SS-mediated disaggregation of CTC clusters was computationally investigated in a vessels-mimicking domain. Finally, CTC clusters were injected within the three different circuits and subjected to the three different WSS, revealing that increasing WSS levels are associated with a raising clusters disaggregation after 6 hours of circulation. These results suggest that our device may represent a valid in vitro tool to carry out systematic studies on the biological significance of blood flow mechanical forces and eventually to promote new strategies for anticancer therapy.

Highlights

Cancer metastasis is a biologically complex tumor dissemination process associated with a poor survival rate
circulating tumor cells (CTCs) are present in the blood of oncologic patients, the amount of these cells is very low if compared with other cells like blood cells or leukocytes [5,6]
CTCs flow the bloodstream as single cells or as multicellular aggregates (CTC clusters), which present with a higher potential to metastasize [7]

Summary

Introduction

Cancer metastasis is a biologically complex tumor dissemination process associated with a poor survival rate. During this process, circulating tumor cells (CTCs) detach from a primary. Hemodynamic shear stress levels disaggregate circulating tumor cells clusters in a microfluidic device tumor and exploit the physiological blood circulation to give origin to metastases at secondary sites [1,2]. Cancer cell motility enables their invasion into the blood vessels, in a phase known as intravasation, to flow through the circulatory system up to reach localized and distant sites [3,4]. CTCs flow the bloodstream as single cells or as multicellular aggregates (CTC clusters), which present with a higher potential to metastasize [7]. When transported in fluids, single CTCs and CTC clusters are subjected to various fluid-dynamic forces affecting cell death or extravasation [8]

Methods

Results

Discussion

Conclusion