Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration

Gonzalez‐Molina, Jordi; Zhang, Xiaoli; Borghesan, Michela; Silva, Joana Mendonça da; Awan, Maooz; Fuller, Barry; Gavara, Núria; Selden, Clare

doi:10.1016/j.biomaterials.2018.05.058

Cited by 70 publications

(36 citation statements)

References 55 publications

(69 reference statements)

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“…HUVECs have long been used in studies of shear stress, showing rapid morphological changes and cell alignment under fluid shear stress conditions 18,19 . SK-HEP-1 cells have been used as a model of a cancer-derived endothelial-like cell 20 and demonstrate enhanced cell migration upon exposure to viscous polymeric solutions 17 . First, we chose high molecular weight (250,000–320,000 g mol −1 ) and high viscosity sodium alginate (Na-alginate) 21 , an inert polymer extensively used as a biomaterial for cell therapy and tissue engineering 22 , since any effects found on endothelial cells may have repercussions on its biomedical applications.…”

Section: Resultsmentioning

confidence: 99%

“…1D,E). However, cell alignment could not be assessed as SK-HEP-1 cells exposed to 1% Na-alginate appeared scattered, an effect that could be a result of a reduced proliferation and enhanced migration 17 . These data show that cells of endothelial origin respond to high macromolecular-content environments and indicate that cancer-derived and normal endothelial cells respond differently to them.…”

Section: Resultsmentioning

confidence: 99%

“…The presence of macromolecules enhances ECM deposition and reaction rates at the cell surface 15,16 . Moreover, high viscosity-inducing macromolecules affect cell-ECM adhesion dynamics in cancer cells 17 .…”

Section: Introductionmentioning

confidence: 99%

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The extracellular fluid macromolecular composition differentially affects cell-substrate adhesion and cell morphology

Gonzalez‐Molina

Silva

Fuller

et al. 2019

Sci Rep

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Soluble macromolecules present in the tumour microenvironment (TME) alter the physical characteristics of the extracellular fluid and can affect cancer cell behaviour. A fundamental step in cancer progression is the formation of a new vascular network which may originate from both pre-existing normal endothelium and cancer-derived cells. To study the role of extracellular macromolecules in the TME affecting endothelial cells we exposed normal and cancer-derived endothelial cells to inert polymer solutions with different physicochemical characteristics. The cancer cell line SK-HEP-1, but not normal human umbilical vein endothelial cells, responded to high-macromolecular-content solutions by elongating and aligning with other cells, an effect that was molecular weight-dependent. Moreover, we found that neither bulk viscosity, osmotic pressure, nor the fractional volume occupancy of polymers alone account for the induction of these effects. Furthermore, these morphological changes were accompanied by an increased extracellular matrix deposition. Conversely, cell-substrate adhesion was enhanced by polymers increasing the bulk viscosity of the culture medium independently of polymer molecular weight. These results show that the complex macromolecular composition of the extracellular fluid strongly influences cancer-derived endothelial cell behaviour, which may be crucial to understanding the role of the TME in cancer progression.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The extracellular fluid macromolecular composition differentially affects cell-substrate adhesion and cell morphology

Gonzalez‐Molina

Silva

Fuller

et al. 2019

Sci Rep

Self Cite

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“…This is for simplicity of numerical computation, as variable viscosities complicate the equations and numerical simulations. Nevertheless, it is instructive to discuss the physical values of the viscosity of the nucleoplasm, cytoplasm and interstitial fluid which could be one to three, and even four orders of magnitude greater than the viscosity of water [ 41 , 42 , 49 – 51 ]. In physical units, this means viscosities from 0.01 to 10 Pa⋅s.…”

Section: Methodsmentioning

confidence: 99%

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

2020

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Cell migration through a three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. By using computer simulations of the cell's mid-plane, we investigate two such migration mechanisms-'push-pull' (forming a fingerlike protrusion, adhering to an ECM node, and pulling the cell body forward) and 'rearsqueezing' (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm, and nucleoplasm. We find that relations between three mechanical parameters-the cortex's contractile force, nuclear elasticity, and ECM rigidity-determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulation results show that nuclear stiffness limits the cell migration more than the ECM rigidity. Simulations show the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values. Additionally, results show that the rear-squeezing mechanism is aided by hydrodynamics through a pressure gradient.

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“…In the simulations, the viscosity is normalised to 1. Nevertheless, it is instructive to discuss the physical values of the viscosity of the nucleoplasm, cytoplasm and interstitial fluid that could be one to three, and even four orders of magnitude greater than of water [36,37,[43][44][45]. In physical units, this means viscosity from 0.01 to 10 Pa·s.…”

Section: Parameter Values and Numerical Proceduresmentioning

confidence: 99%

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

Maxian

Mogilner

Strychalski

2020

Preprint

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Cell migration through three-dimensional (3D) extracellular matrix (ECM) underlies important physiological phenomena and is based on a variety of mechanical strategies depending on the cell type and the properties of the ECM. By using computer simulations, we investigate two such migration mechanisms -'push-pull' (forming a finger-like protrusion, adhering to an ECM node, and pulling the cell body forward) and 'rear-squeezing' (pushing the cell body through the ECM by contracting the cell cortex and ECM at the cell rear). We present a computational model that accounts for both elastic deformation and forces of the ECM, an active cell cortex and nucleus, and for hydrodynamic forces and flow of the extracellular fluid, cytoplasm and nucleoplasm. We find that relations between three mechanical parameters -the cortex's contractile force, nuclear elasticity and ECM rigidity -determine the effectiveness of cell migration through the dense ECM. The cell can migrate persistently even if its cortical contraction cannot deform a near-rigid ECM, but then the contraction of the cortex has to be able to sufficiently deform the nucleus. The cell can also migrate even if it fails to deform a stiff nucleus, but then it has to be able to sufficiently deform the ECM. Simulation results show that nuclear stiffness limits the cell migration more than the ECM rigidity. Simulations of the rear-squeezing mechanism of motility results in more robust migration with larger cell displacements than those with the push-pull mechanism over a range of parameter values. Author summaryComputational simulations of models representing two different mechanisms of 3D cell migration in an extracellular matrix are presented. One mechanism represents a mesenchymal mode, characterized by finger-like actin protrusions, while the second mode is more amoeboid in that rear contraction of the cortex propels the cell forward. In both mechanisms, the cell generates a thin actin protrusion on the cortex that attaches to an ECM node. The cell is then either pulled (mesenchymal) or pushed (amoeboid) forward. Results show both mechanisms result in successful migration over a range of simulated parameter values as long as the contractile tension of the cortex exceeds either the nuclear stiffness or ECM stiffness, but not necessarily both. However, January 20, 2020 1/25 the distance traveled by the amoeboid migration mode is more robust to changes in parameter values, and is larger than in simulations of the mesenchymal mode. Additionally cells experience a favorable fluid pressure gradient when migrating in the amoeboid mode, and an adverse fluid pressure gradient in the mesenchymal mode.

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Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration

Cited by 70 publications

References 55 publications

The extracellular fluid macromolecular composition differentially affects cell-substrate adhesion and cell morphology

The extracellular fluid macromolecular composition differentially affects cell-substrate adhesion and cell morphology

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

Computational estimates of mechanical constraints on cell migration through the extracellular matrix

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