How Tumor Cells Can Make Use of Interstitial Fluid Flow in a Strategy for Metastasis

Abstract

Introduction-The phenomenon of lymph node metastasis has been known for a long time. However, the underlying mechanism by which malignant tumor cells are able to break loose from the primary tumor site remains unclear. In particular, two competing fluid sensitive migration mechanisms have been reported in the experimental literature: (i) autologous chemotaxis (Shields et al. in Cancer Cell 11:526-538, 2007) which gives rise to downstream migration; (ii) an integrin-mediated and strain-induced upstream mechanism (Polacheck et al. in PNAS 108:11115-11120, 2011). How can these two competing mechanisms be used as a means for metastatic behavior in a realistic tumor setting? Excessive fluid flow is typically produced from leaky intratumoral blood vessels and collected by lymphatics in the peritumoral region giving rise to a heterogeneous fluid velocity field and a corresponding heterogeneous cell migration behavior, quite different from the experimental setup. Method-In order to shed light on this issue there is a need for tools which allow one to extrapolate the observed single cell behavior in a homogeneous microfluidic environment to a more realistic, higher-dimensional tumor setting. Here we explore this issue by using a computational multiphase model. The model has been trained with data from the experimental results mentioned above which essentially reflect one-dimensional behavior. We extend the model to an envisioned idealized two-dimensional tumor setting. Result-A main observation from the simulation is that the autologous chemotaxis migration mechanism, which triggers tumor cells to go with the flow in the direction of lymphatics, becomes much more aggressive and effective as a means for metastasis in the presence of realistic IF flow. This is because the outwardly directed IF flow generates upstream cell migration that possibly empowers small clusters of tumor cells to break loose from the primary tumor periphery. Without this upstream stress-mediated migration, autologous chemotaxis is inclined to move cells at the rim of the tumor in a homogeneous and collective, but space-demanding style. In contrast, inclusion of realistic IF flow generates upstream migration that allows two different aspects to be synthesized: maintain the coherency and solidity of the the primary tumor and at the same time cleave the outgoing waves of tumor cells into small clusters at the front that can move collectively in a more specific direction.

Mathematical Analysis of Two Competing Cancer Cell Migration Mechanisms Driven by Interstitial Fluid Flow

“…A rather general cell-fluid-ECM model was proposed in Waldeland and Evje (2018a) and further developed in Waldeland and Evje (2018b) and Evje and Waldeland (2019) to shed light on the above-mentioned competing cell migration mechanisms governed by interstitial fluid flow. A gently simplified version of the model, where we ignore certain details of the biochemical part by assuming that chemokine C is directly produced by the tumor cells instead of being released from ECM, takes the following form:…”

A fully-decoupled discontinuous Galerkin approximation of the Cahn–Hilliard–Brinkman–Ohta–Kawasaki tumor growth model

“…But it is worth noting that many developed models omit the actual interstitial fluid pressure [1,28,43,59] or just treat it as a fixed function (or constant) [30,37,52,64], although many physiological results suggest that tumor interstitial fluid pressure is a very important factor that can affect tumor prognosis, treatment, metastasis, and drug delivery, cf. [4,16,31,33,35,38,48]. This prompts us to develop a comprehensive mathematical model to incorporate more details, especially the fluid pressure, to provide further insights into describing, understanding, and predicting tumor evolution.…”

Progression of Metastasis through Lymphatic System

“…Intriguingly, Evje et al used a computational simulation to interpret how these competing mechanisms—CCR7-dependent autologous chemotaxis and CCR7-independent upstream migration—can both contribute to LN metastasis. The simulations predict that flow-mediated autologous chemotaxis initiates tumor migration towards lymphatics, while upstream migration enables small clusters to detach from the primary tumor [ 53 ]. Additionally, Sheih et al determined that interstitial flow stimulates TGF-β- and MMP-dependent migration of fibroblasts in a 3D invasion assay.…”