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The physics of cancer: the role of physical interactions and mechanical forces in metastasis

Abstract

Metastasis is a complex, multistep process responsible for >90% of cancer-related deaths. In addition to genetic and external environmental factors, the physical interactions of cancer cells with their microenvironment, as well as their modulation by mechanical forces, are key determinants of the metastatic process. We reconstruct the metastatic process and describe the importance of key physical and mechanical processes at each step of the cascade. The emerging insight into these physical interactions may help to solve some long-standing questions in disease progression and may lead to new approaches to developing cancer diagnostics and therapies.

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Figure 1: The metastatic process.
Figure 2: The physics of invasion and intravasation.
Figure 3: Arrest of circulating tumour cells.
Figure 4: Capture and arrest of circulating tumour cells.

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Acknowledgements

The authors gratefully acknowledge support from the US National Institutes of Health (grants U54CA143868, U54CA151838 and RO1CA101135).

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Glossary

Amoeboid migration

A mode of three-dimensional cell migration in a matrix that involves dynamic cell-shape changes through actomyosin assembly and contractility, and adhesion to the extracellular matrix.

Epithelial-to-mesenchymal transition

(EMT). A morphological change that epithelial cells undergo, from a cubical to an elongated shape, following oncogenic transformation, which is often accompanied by loss of expression of the adhesion molecule E-cadherin. Post-EMT, cells adopt a high-motility phenotype.

Filopodia

Narrow projections of the cytoplasm extended beyond the lamellipodia of migrating cells. Filopodia are associated with the formation of nascent focal adhesions with a substratum.

Focal adhesions

Integrin clusters located at the basal surface of adherent cells that connect the extracellular matrix to the cytoskeleton through focal adhesion proteins.

Interstitial flow

Fluid flow in the extracellular matrix, often associated with lymphatic drainage of plasma back to the vascular system.

Intravital microscopy

A microscopy technique used for the observation of biological responses, such as leukocyteendothelial cell interactions, in living tissues in real time. Translucent tissues are commonly used, such as the mesentery or cremaster muscle, which can be easily exteriorized for microscopic observation.

Lamellipodia

Large cytoplasmic projects found primarily at the leading edge of migrating cells, particularly on two-dimensional substrates.

Mechanosensing

The ability of cells to sense and respond to changes in the mechanical compliance of a substrate. Mechanosensing is mediated by focal adhesions and the cytoskeleton in two-dimensional cell culture.

Mesenchymal migration

A mode of three-dimensional cell migration in a matrix that involves integrin-based adhesion. Mesenchymal migration occurs when the pore size of the matrix is much smaller than the cell nucleus.

Pseudopodia

Bulges of constantly changing shape observed in the plasma membrane of migrating cells during amoeboid migration on two-dimensional substrates and mesenchymal migration through three-dimensional matrices.

Shear rate

The relative velocities of adjacent layers of fluid under shear force in conditions of laminar flow.

Shear stress

The magnitude of the tangential force applied onto the surface of an object per unit area. Shear stress is expressed in units of force per unit area (Newtons m−2 in metres kilograms seconds (MKS) units or dynes cm−2 in centimetres grams seconds (CGS) units).

Stiffness

(Also known as elasticity or elastic modulus). A measure of the ability of a material to resist shear forces similarly to a solid. Rubber is elastic and shows little viscosity. A crosslinked collagen matrix is elastic, but not viscous as it does not flow. The cytoplasm of cells is both elastic and viscous (viscoelastic) depending on the rate of deformation.

Stress fibres

Contractile actin filament bundles that contain myosin II, which serves both as an F-actin bundling protein and as a force generator. Stress fibres terminate at focal adhesions at the basal surface of cells on substrates.

Surface tangential velocity

The velocity at the surface of a spinning object.

Translational velocity

The velocity of an object in space.

Viscosity

A measure of the ability of a material to flow like a liquid. Water, glycerol and honey are liquids of increasing viscosity; they are only viscous and show no elasticity.

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Wirtz, D., Konstantopoulos, K. & Searson, P. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat Rev Cancer 11, 512–522 (2011). https://doi.org/10.1038/nrc3080

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