In Vitro Model of Tumor Cell Extravasation

Abstract

Tumor cells that disseminate from the primary tumor and survive the vascular system can eventually extravasate across the endothelium to metastasize at a secondary site. In this study, we developed a microfluidic system to mimic tumor cell extravasation where cancer cells can transmigrate across an endothelial monolayer into a hydrogel that models the extracellular space. The experimental protocol is optimized to ensure the formation of an intact endothelium prior to the introduction of tumor cells and also to observe tumor cell extravasation by having a suitable tumor seeding density. Extravasation is observed for 38.8% of the tumor cells in contact with the endothelium within 1 day after their introduction. Permeability of the EC monolayer as measured by the diffusion of fluorescently-labeled dextran across the monolayer increased 3.8 fold 24 hours after introducing tumor cells, suggesting that the presence of tumor cells increases endothelial permeability. The percent of tumor cells extravasated remained nearly constant from1 to 3 days after tumor seeding, indicating extravasation in our system generally occurs within the first 24 hours of tumor cell contact with the endothelium.

Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation

“…cancer cell migration, adhesion (23), and extravasation (24,25). Recently, our group presented a microfluidic model to investigate the specificity of breast cancer metastasis to bone, providing quantitative data on cancer cell extravasation rate and reproducing the effects of the CXCL5-CXCR2 interaction between bone cells and metastatic breast cancer cells observed in vivo (26).…”

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

“…Recently, several studies using microfluidic platform have been reported that recreate the 3D context of each aspect of the TME and metastasis in vitro. [10][11][12][13] However, to our knowledge, no versatile in vitro experimental model that reconstitutes direct interplay between constituents of the TME during tumorigenesis has yet been reported. Here we describe a biomimetic TME model to mimic the complex inter actions of the tumor, stromal, and endothe lial cells, all of which are essential components of the TME that hinder the effective treatment of cancers.…”

The Role of EphB4 and Ephrin-B2 Interactions in Prostate Cancer Models of Intravasation and Extravasation

“…The process consists of TC transport via the blood circulation, survival of the shear stress, arrest and attachment to a vessel wall and trans-endothelial invasion across the vessel wall and into the secondary metastatic site [54]. Two possible modes have been proposed…”

“…The first, as described in the famous hypothesis by Paget, proposes that tumours of different organs show unique patterns of metastatic colonisation (seed) to other specific organ microenvironments (soil) through site-selective adhesion [45,54,55]. The second mode of extravasation hypothesises that due to the slightly larger size of TCs and their ability to aggregate with platelets, they become trapped in small vessels and capillary beds [56,57].…”

“…The second mode of extravasation hypothesises that due to the slightly larger size of TCs and their ability to aggregate with platelets, they become trapped in small vessels and capillary beds [56,57]. Both modes have been observed during extravasation [58][59][60], however it is unclear as to which is the preferential mode and whether there are selective characteristics of TCs that promote a particular type of arrest [54].…”