Abstract
Metastasis is a dynamic succession of events involving the dissemination of tumour cells to distant sites within the body, ultimately reducing the survival of patients with cancer. To colonize distant organs and, therefore, systemically disseminate within the organism, cancer cells and associated factors exploit several bodily fluid systems, which provide a natural transportation route. Indeed, the flow mechanics of the blood and lymphatic circulatory systems can be co-opted to improve the efficiency of cancer cell transit from the primary tumour, extravasation and metastatic seeding. Flow rates, vessel size and shear stress can all influence the survival of cancer cells in the circulation and control organotropic seeding patterns. Thus, in addition to using these fluids as a means to travel throughout the body, cancer cells exploit the underlying physical forces within these fluids to successfully seed distant metastases. In this Review, we describe how circulating tumour cells and tumour-associated factors leverage bodily fluids, their underlying forces and imposed stresses during metastasis. As the contribution of bodily fluids and their mechanics raises interesting questions about the biology of the metastatic cascade, an improved understanding of this process might provide a new avenue for targeting cancer cells in transit.
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Acknowledgements
D.H. acknowledges support from the Cancer Institute of New South Wales (CINSW) Fellowship and project grants from the National Breast Cancer Foundation (NBCF), St. Vincent’s Clinic Foundation and Sydney Catalyst (the Translational Cancer Research Centre of central Sydney and regional New South Wales). S.W. acknowledges support from National Health and Medical Research Council (NHMRC) Project Grants and Suttons. P.T. acknowledges support from an NHMRC fellowship, NHMRC project grants and a Len Ainsworth Pancreatic Cancer Fellowship. This project was made possible by an Avner Pancreatic Cancer Foundation Grant. The authors thank all members of the Goetz Lab for helpful discussions. Work related to this Review in the Goetz Lab (G.F., N.O., V.H., S.H. and J.G.G.) is funded by the French National Cancer Institute (INCa) and Plan Cancer, and by institutional funds from INSERM and the University of Strasbourg. N.O. acknowledges support from Plan Cancer 2014–2019 (OptoMetaTrap) and the Association pour la Recherche Contre le Cancer (ARC). G.F. is supported by La Ligue Contre le Cancer and the University of Strasbourg.
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G.F., D.H., N.O., S.H., V.H., P.T. and J.G.G. researched data for the article. All authors made substantial contributions to the discussion of content, wrote the manuscript and reviewed and/or edited the manuscript before submission.
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Glossary
- Fluids
-
Substances devoid of rigidity that continuously deform and do not resist shear stress applied to them.
- Interstitial fluid
-
Fluid originating from blood capillaries’ leakiness that is present around cells, bringing nutrients to these cells and flowing towards lymphatic draining sites, giving rise to interstitial fluid flow.
- Circulating tumour cells
-
(CTCs). Tumour cells that have left their primary tumour and entered the blood or lymphatic circulation (intravasation); to survive and to travel throughout the body, they co-opt this new fluid environment that they are exposed to.
- Soluble factors
-
Proteins (including protein ligands or extracellular matrix-modifying proteins) that are secreted by tumour cells to induce the remodelling of distant sites to facilitate metastatic seeding.
- Extracellular vesicles
-
(EVs). Lipid bilayer-delimited particles that serve as cargo for the transfer of nucleic acids, proteins or lipids to distant sites; their membrane composition provides a fingerprint for the targeted priming of specific organs.
- Intravascular arrest
-
The process that precedes cancer cell extravasation, whereby circulating tumour cells become physically occluded in microvessels and/or actively adhere to the inner endothelial lining of blood vessels at secondary sites.
- Pre-metastatic niches
-
(PMNs). A new paradigm for the initiation of metastasis; these are pre-metastatic microenvironments that are seeded and/or educated by tumour-secreted factors, inducing phenotypes that can help secondary tumour development.
- Reynolds number
-
(Re). A dimensionless number proportional to fluid velocity V, density ρ, the displacement length L and the viscosity η. It allows one to classify flow types and to determine whether the fluid flow is laminar or turbulent (Re > 1000).
- Laminar flow
-
In fluid dynamics, fluid particles transported in a laminar flow follow smooth directions in layers, with little or no mixing.
- Viscosity
-
A measure of the resistance of a fluid to deformation at a given rate that quantifies the frictional force generated by layers of fluids that are in motion. Gases, water and other liquids are considered Newtonian fluids because they display a linear correlation between shear stress and the rate of deformation. When fluids display a non-linear relation between stress and the deformation rate, they are considered non-Newtonian — this is the case for blood.
- Turbulent flow
-
In contrast to laminar flow, turbulent flow is characterized by chaotic changes in pressure and flow velocity that create mixing of the flow paths of displaced particles.
- Darcy’s law
-
A physical law that, in the context of cancer progression, is linked to interstitial fluid and to hydraulic conductivity of the environment arising from a convective fluid displacement.
- Hydraulic conductance
-
The capacity of a porous material to allow fluid to cross under the effect of pressure differences.
- Interstitial fluid pressure
-
(IFP). The hydrostatic pressure in the cellular interstice, which, in solid tumours, is often due to vessel leakage and lymphatic drainage.
- Lymphangiogenesis
-
The remodelling of existing lymphatic networks to give rise to new lymphatic vessels.
- Solid stress
-
A stress exerted by the solid constituents of a tissue that accumulate within solid structural components (for example, extracellular matrix and tumour and stromal cells) during tumour growth.
- Convective flow
-
A flow directed towards a gradient; in the case of a solid tumour, this is a pressure gradient.
- Shear stress
-
A pressure that creates deformation when moving tangentially to a surface; for example, shear stress is generated when fluids flow over an endothelial surface.
- Margination
-
A physical process that brings cells or vesicles close to the endothelial wall.
- Exomeres
-
A type of extracellular vesicle that is characterized by small size (~35 nm) and the absence of a membrane; exomeres are enriched in metabolic enzymes and hypoxia-related, microtubule-related and coagulation proteins.
- Oncosomes
-
A subtype of large membrane-derived extracellular vesicles (microvesicles) secreted by cancer cells that transfer oncogenic molecules to other cells.
- Hagen–Poiseuille equation
-
This equation describes the velocity in a laminar regime for a viscous fluid moving in a cylindrical tube as a quadratic distribution.
- Inertia
-
The extent to which cells and other material can maintain their motion against the flow.
- Viscoelasticity
-
This term defines a material that exhibits elastic and viscous behaviour when placed under stress.
- Fluid-structure behaviour
-
This behaviour occurs when the fluid deforms a physical structure, which will, in turn, modify the fluid flow.
- Ramification
-
A process that occurs in the vasculature when a stem vessel is branching out into two smaller-sized vessels.
- Metastable
-
A state of least energy until more external energy is added to the system; this state seems to be stable, although it is, in theory, unstable and capable of changing to a more stable state.
- Thrombocytopenia
-
A condition characterized by low platelet count.
- Bell’s model
-
A statistical model taking into account the chemical rates of formation and dissociation between ligands and receptors as well as the statistical distribution of these ligand–receptor pairs on two cell surfaces when external forces are applied.
- Diapedesis
-
The transmigration process by which circulating cells exit the bloodstream using either the transcellular (through endothelial cells) or the paracellular (between endothelial cells through cell–cell junctions) route.
- Catch bonds
-
Receptor–ligand interactions, the strength and lifetime of which increases under applied force.
- Cytoplasts
-
Nucleus-free portions of cells that are released from arrested circulating tumour cells when facing high shear forces.
- Necroptosis
-
A process that induces cell death through controlled necrosis.
- Endothelial remodelling
-
A process that represents the ability of endothelial cells to sense and respond to stimuli (such as fluid flow, shear stress and trafficking of immune cells) by remodelling their contact adhesion to move towards specific reorganization, leading to flow homeostasis.
- Liquid biopsy
-
The collection of non-solid tissues, such as blood, and screening it for disease-related parameters, such as circulating tumour cells. In contrast to biopsy of solid internal tissues, liquid biopsy is minimally invasive and suited for repeated assessment in the same patient.
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Follain, G., Herrmann, D., Harlepp, S. et al. Fluids and their mechanics in tumour transit: shaping metastasis. Nat Rev Cancer 20, 107–124 (2020). https://doi.org/10.1038/s41568-019-0221-x
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DOI: https://doi.org/10.1038/s41568-019-0221-x
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Distinguishing high-metastasis-potential circulating tumor cells through fluidic shear stress in a bloodstream-like microfluidic circulatory system
Oncogene (2024)
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Multiplex, high-throughput method to study cancer and immune cell mechanotransduction
Communications Biology (2024)
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Experimental measurement and numerical modeling of deformation behavior of breast cancer cells passing through constricted microfluidic channels
Microsystems & Nanoengineering (2024)