Competing tumor cell migration mechanisms caused by interstitial fluid flow

Waldeland, Jahn Otto; Evje, Steinar

doi:10.1016/j.jbiomech.2018.09.011

Cited by 20 publications

(12 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interstitial pressure and associated interstitial flow, being hallmarks of PDAC, are bound to have other profound effects on the cancer cells that contribute to PDAC pathogenesis, in addition to their effects on MRP function and expression. For example, interstitial flow has been linked to the migratory behavior of cancer cells in biological, as well as mathematical models [34]. These results suggest that there are competing tumor cell migration mechanisms that occur due to interstitial flow, a CCR7-dependent mechanism that induces downstream migration and a CCR7-independent mechanism that promotes cells to migrate upstream.…”

Section: Discussionmentioning

confidence: 99%

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

Kramer

Haan

Vermeer

et al. 2019

IJMS

View full text Add to dashboard Cite

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline.

show abstract

Section: Discussionmentioning

confidence: 99%

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

Kramer

Haan

Vermeer

et al. 2019

IJMS

View full text Add to dashboard Cite

show abstract

“…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:…”

Section: A General Cell-fluid-ecm Modelmentioning

confidence: 99%

“…From the two momentum equations (1.1) 3,4 , we can compute explicit expressions for the cell and fluid velocity, respectively, u c and u w (Waldeland and Evje 2018a). The following expressions are found: 3) used in Waldeland and Evje (2018b) and where the total velocity U T = α c u c + α w u w is determined from the equation U T = −λ T ∇ P w −λ c ∇( P + ) and the fact that ∇ •U T = 0. We refer to Waldeland and Evje (2018a) for details.…”

Section: A General Cell-fluid-ecm Modelmentioning

confidence: 99%

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

Evje

Winkler

2020

J Nonlinear Sci

Self Cite

View full text Add to dashboard Cite

Recent experimental work has revealed that interstitial fluid flow can mobilize two types of tumor cell migration mechanisms. One is a chemotactic-driven mechanism where chemokine (chemical component) bounded to the extracellular matrix (ECM) is released and skewed in the flow direction. This leads to higher chemical concentrations downstream which the tumor cells can sense and migrate toward. The other is a mechanism where the flowing fluid imposes a stress on the tumor cells which triggers them to go in the upstream direction. Researchers have suggested that these two migration modes possibly can play a role in metastatic behavior, i.e., the process where tumor cells are able to break loose from the primary tumor and move to nearby lymphatic vessels. In Waldeland and Evje (J Biomech 81:22-35, 2018), a mathematical cell-fluid model was put forward based on a mixture theory formulation. It was demonstrated that the model was able to capture the main characteristics of the two competing migration mechanisms. The objective of the current work is to seek deeper insight into certain qualitative aspects of these competing mechanisms by means of mathematical methods. For that purpose, we propose a simpler version of the cell-fluid model mentioned above but such that the two competing migration mechanisms are retained. An initial cell distribution in a one-dimensional slab is exposed to a constant fluid flow from one end to the other, consistent with the experimental setup. Then, we explore by means of analytical estimates the long-time behavior of the two competing migration mechanisms for two different scenarios: (i) when the initial cell volume fraction is low and (ii) when the initial cell volume fraction is high. In particular, it is demonstrated in a strict mathematical sense that for a sufficiently low initial cell volume fraction, the downstream migration dominates in the sense that the solution converges to a downstream-dominated steady state as time elapses. On the other hand, with a sufficiently high initial cell volume fraction, the upstream migration mechanism is the stronger in the sense that the solution converges to an upstream-dominated steady state. Communicated by Alain Goriely.

show abstract

“…This was carefully explored in the two recent works. 35,36 Through that study, the model was trained with data from relevant in vitro experiments and insight was gained for setting various model parameters. However, the experimental setup in Refs.…”

Section: Methodsmentioning

confidence: 99%

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

Evje

Waldeland

2019

Cel. Mol. Bioeng.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Competing tumor cell migration mechanisms caused by interstitial fluid flow

Cited by 20 publications

References 16 publications

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

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

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

Contact Info

Product

Resources

About