Abstract
Cellular exosome-mediated crosstalk in tumor microenvironment (TME) is a critical component of anti-tumor immune responses. In addition to particle size, exosome transport and uptake by target cells is influenced by physical and physiological factors, including interstitial fluid pressure, and exosome concentration. These variables differ under both normal and pathological conditions, including cancer. The transport of exosomes in TME is governed by interstitial flow and diffusion. Based on these determinants, mathematical models were adapted to simulate the transport of exosomes in the TME with specified exosome release rates from the tumor cells. In this study, the significance of spatial relationship in exosome-mediated intercellular communication was established by treating their movement in the TME as a continuum using a transport equation, with advection due to interstitial flow and diffusion due to concentration gradients. To quantify the rate of release of exosomes by biomechanical forces acting on the tumor cells, we used a transwell platform with confluent triple negative breast cancer cells 4T1.2 seeded in BioFlex plates exposed to an oscillatory force. Exosome release rates were quantified from 4T1.2 cells seeded at the bottom of the well following the application of either no force or an oscillatory force, and these rates were used to model exosome transport in the transwell. The simulations predicted that a larger number of exosomes reached the membrane of the transwell for 4T1.2 cells exposed to the oscillatory force when compared to controls. Additionally, we simulated the interstitial fluid flow and exosome transport in a 2-dimensional TME with macrophages, T cells, and mixtures of these two populations at two different stages of a tumor growth. Computational simulations were carried out using the commercial computational simulation package, ANSYS/Fluent. The results of this study indicated higher exosome concentrations and larger interstitial fluid pressure at the later stages of the tumor growth. Quantifying the release of exosomes by cancer cells, their transport through the TME, and their concentration in TME will afford a deeper understanding of the mechanisms of these interactions and aid in deriving predictive models for therapeutic intervention.
Highlights
The tumor microenvironment (TME), which contains multiple cell types, blood and lymph vessels, and extracellular matrix (ECM), is often immunosuppressive, blocking anti-tumor immunity, and mediating drug resistance [1]
As a key mediator of cell-cell signaling within the TME, tumor cell exosomes have emerged as important regulators of several aspects of tumor progression [5], including tumor initiation, progression and invasion, and preparation of pre-metastatic niches [6, 7]
The cells that release exosomes were placed at the bottom chamber and the release rates of the exosomes from these cells were taken from the experiments described in the previous section
Summary
The tumor microenvironment (TME), which contains multiple cell types, blood and lymph vessels, and extracellular matrix (ECM), is often immunosuppressive, blocking anti-tumor immunity, and mediating drug resistance [1]. As a key mediator of cell-cell signaling within the TME, tumor cell exosomes have emerged as important regulators of several aspects of tumor progression [5], including tumor initiation, progression and invasion, and preparation of pre-metastatic niches [6, 7]. We and others have demonstrated that tumor-derived exosomes promote macrophages polarization [9,10,11]. They contribute to immune regulation and can create an immuno-privileged environment within tumors [8, 12]
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