High Shear Stresses under Exercise Condition Destroy Circulating Tumor Cells in a Microfluidic System

Sagar Regmi,Afu Fu,Kathy Qian Luo

doi:10.1038/srep39975

Sagar Regmi, Afu Fu + Show 1 more

Open Access

https://doi.org/10.1038/srep39975

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Abstract

Circulating tumor cells (CTCs) are the primary targets of cancer treatment as they cause distal metastasis. However, how CTCs response to exercise-induced high shear stress is largely unknown. To study the effects of hemodynamic microenvironment on CTCs, we designed a microfluidic circulatory system that produces exercise relevant shear stresses. We explore the effects of shear stresses on breast cancer cells with different metastatic abilities, cancer cells of ovarian, lung and leukemic origin. Three major findings were obtained. 1) High shear stress of 60 dynes/cm2 achievable during intensive exercise killed more CTCs than low shear stress of 15 dynes/cm2 present in human arteries at the resting state. 2) High shear stress caused necrosis in over 90% of CTCs within the first 4 h of circulation. More importantly, the CTCs that survived the first 4 h-circulation, underwent apoptosis during 16–24 h of post-circulation incubation. 3) Prolonged high shear stress treatment effectively reduced the viability of highly metastatic and drug resistant breast cancer cells. As high shear stress had much less damaging effects on leukemic cells mimicking the white blood cells, we propose that intensive exercise may be a good strategy for generating high shear stress that can destroy CTCs and prevent cancer metastasis.

Highlights

CTCs can potentially be destroyed in the bloodstream by several mechanisms including hemodynamic shear stress (SS), anoikis due to the detachment of the CTCs from the extracellular matrix, and immune-elimination[11]
Hemodynamic SS is the main focus of this study because it has been reported that SS generated by the bloodstream can destroy cancer cells, rendering the metastatic process ineffective[2,12]
Few studies investigated the destructive effects of SS on CTCs, whose survival is a prerequisite for metastasis

Summary

Introduction

CTCs can potentially be destroyed in the bloodstream by several mechanisms including hemodynamic shear stress (SS), anoikis due to the detachment of the CTCs from the extracellular matrix, and immune-elimination[11]. We reported that physiological levels of SS could induce apoptosis in circulating breast cancer cells[18] It is not well understood how high levels of SS achievable under intensive exercise conditions can affect CTCs, especially the ones with increased levels of malignancy. To address this question, we have developed a bio-mimicking circulatory system that can produce a broader range of SS than the one reported in our previous study[18]. By combining the three technologies including the microfluidic circulatory system, metastatic cell lines, and apoptotic sensor, we were able to closely examine how high SS generated during intensive exercise destroys CTCs

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