Fluid Shear Stress Effects on Cancer Metastasis

Abstract

Metastasis is responsible for at least 66% of cancer-related deaths, yet it remains a poorly understood phenomenon. Fluid shear stress is common to all metastatic events but its effects on circulating tumor cells (CTCs) remains a mystery. It is known that shear stress can act either directly, causing membrane rupture and cell death, or by altering cell phenotype via mechanotransduction pathways, but to what extent these and other unknown effects have on the metastatic cascade remains unresolved. In vivo models have been limited in their ability to effectively study this problem largely because of the challenges in tracking TCs in the circulation and poor control over the flow environment. In vitro platforms with fluid flow are not physiologically relevant due to their 2D nature and the requirement for large bulk volume, and their inability to recapitulate the entire metastatic cascade. Here, an in vitro flow system that allows circulation of cells through physiologically relevant 3D microvasculature in presence or absence of tumor spheroids and organoids that addresses the limitations of current models is presented. The flow system was first used solely with MVNs. Applying flow at a magnitude comparable to physiological levels of FSS resulted in fully perfusable MVNs and flow magnitude-dependent vessel remodelling. Flow also increases the lifespan of MVNS three-fold compared to static culture. Furthermore, higher flow resulted in fewer arrested TCs and a larger fraction of extravasated and proliferated TCs. Finally, we are able to support metastatic outgrowths up to 1000 um in diameter. The system can be further expanded to incorporate more steps of the metastatic cascade, study the differences in survivability of single TCs or TC clusters, and use surgical samples to probe patient variability. This platform allows for a controlled method of investigating the effects of fluid shear stress on the metastatic cascade and can reveal potential anti-cancer therapeutic targets.