Abstract
Metastasis is a dynamic process involving the dissemination of circulating tumor cells (CTCs) through blood flow to distant tissues within the body. Nevertheless, the development of an in vitro platform that dissects the crucial steps of metastatic cascade still remains a challenge. We here developed an in vitro model of extravasation composed of (i) a single channel-based 3D cell laden hydrogel representative of the metastatic site, (ii) a circulation system recapitulating the bloodstream where CTCs can flow. Two polymers (i.e., fibrin and alginate) were tested and compared in terms of mechanical and biochemical proprieties. Computational fluid-dynamic (CFD) simulations were also performed to predict the fluid dynamics within the polymeric matrix and, consequently, the optimal culture conditions. Next, once the platform was validated through perfusion tests by fluidically connecting the hydrogels with the external circuit, highly metastatic breast cancer cells (MDA-MB-231) were injected and exposed to physiological wall shear stress (WSS) conditions (5 Dyn/cm2) to assess their migration toward the hydrogel. Results indicated that CTCs arrested and colonized the polymeric matrix, showing that this platform can be an effective fluidic system to model the first steps occurring during the metastatic cascade as well as a potential tool to in vitro elucidate the contribution of hemodynamics on cancer dissemination to a secondary site.
Highlights
Circulating tumor cells (CTCs) are viable cells that circulate in the bloodstream after detaching from a primary tumor [1]
A simulation of the mass transport process occurring between the medium and the hydrogels was performed by employing the Transport of the diluted species (TDS) module of Comsol Multiphysics (COMSOL AB, Stockholm, Sweden) in order to fit the raw data and to get the optimal glucose diffusion coefficient by comparing the two resulting curves
To obtain a tumor extracellular matrix (ECM)-like model traversed by a perfusable channel, a hydrogel matrix with a single inner vessel-like channel fluidically connected to an external circuit was realized (Figure 1) in single inner vessel-like channel fluidically connected to an external circuit was realized (Figure 1) in order to study the first steps occurring during the metastatic cascade
Summary
Circulating tumor cells (CTCs) are viable cells that circulate in the bloodstream after detaching from a primary tumor [1]. Different studies showed that these cells play a key role in tumor progression [2]. It was shown a correlation between the presence of circulating tumor cells with a short survival rate of patients with metastatic carcinoma [3,4]. During the process of metastasis, tumor cells intravasate into bloodstream and lymphatic vessels, translocate until reaching distant tissues, to extravasate, attach and proliferate, giving origin to a metastatic site [5].
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