The Use of Microfluidic Platforms to Probe the Mechanism of Cancer Cell Extravasation

Abstract

Powerful experimental tools have contributed a wealth of novel insight into cancer etiology from the organ to the subcellular levels. However, these advances in understanding have outpaced improvements in clinical outcomes. One possible reason for this shortcoming is the reliance on animal models that do not fully replicate human physiology. An alternative in vitro approach that has recently emerged features engineered microfluidic platforms to investigate cancer progression. These devices allow precise control over cellular components, extracellular constituents, and physical forces, while facilitating detailed microscopic analysis of the metastatic process. This review focuses on the recent use of microfluidic platforms to investigate the mechanism of cancer cell extravasation.

Remodeling of the Microvasculature: May the Blood Flow Be With You

“…The possibility to control and model computationally both the biochemical and physical gradients ( Nguyen et al, 2013 ) and the flow and shear stress distribution, timing and ramping along the device ( Chiu and Chien, 2011 ) makes it possible to establish correlations between the different types of stimuli and the endothelial cell response. Given that intraluminal endothelial migration occurs in contact with the preserved basement membrane during capillary remodeling, it is worth mentioning that microfluidic systems including a basement membrane have been implemented for the study of endothelial cell permeability or cancer metastasis ( Han et al, 2015 ; Kim et al, 2019 ; Coughlin and Kamm, 2020 ).…”

Glycocalyx-Mediated Vascular Dissemination of Circulating Tumor Cells

“…As vascular dissemination represents the rate-limiting step in 10 metastasis 13 , uncovering mechanisms of interaction between TCs and endothelial cells (ECs) may 11 reveal crucial therapeutic opportunities. 12 The extravasation of TCs includes two necessary and sequential steps: arrest under blood flow and 13 trans-endothelial migration 14 . Both processes have largely been studied in terms of the molecules 14 mediating specific adhesive interactions between TCs and ECs 15 .…”

“…12 The extravasation of TCs includes two necessary and sequential steps: arrest under blood flow and 13 trans-endothelial migration 14 . Both processes have largely been studied in terms of the molecules 14 mediating specific adhesive interactions between TCs and ECs 15 . Remarkably, the EC adhesion 15 molecules identified (e.g.…”

“…24 Direct observations of extravasation in vivo have been conducted in animal models, which may have 25 limited relevance to human biology 24 and present intrinsic difficulties in visualization of rapid 26 interactions between TCs and ECs. Therefore, in order to assess relevant TC extravasation 27 mechanisms, advanced experimental systems are required to recapitulate human physiology while 28 allowing for high spatiotemporal resolution imaging of cell interactions 14,25,26 . Our research group has 29 developed and used perfusable microvascular networks (MVNs) self-assembled from human ECs and 30 stromal cells within microfluidic devices 27 , which have been employed in the past to explore the role 31 of specific adhesion molecules, such as integrins, expressed on TCs 28 .…”

Engineering approaches for studying immune-tumor cell interactions and immunotherapy

“…Recently, researchers have also studied extravasation of circulating tumor cells by perfusing tumor cells into 3D microvascular networks ( Coughlin and Kamm, 2020 ). In particular, a microfluidic vasculature with physiological levels of flow was employed to demonstrate that primary neutrophils clustered in the vicinity of tumor cells (A375-MA2 melanoma) in the microvessels and enhanced their rate of extravasation, mediated by a combination of neutrophil-secreted IL-8 and tumor-cell-secreted CXCL-1 ( Chen et al., 2018 ).…”