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A tense situation: forcing tumour progression

Key Points

  • Cells within tissues are continuously exposed to physical forces, including hydrostatic pressure, shear stress and compression and tension forces. The nature of these forces can change in pathologies such as cardiovascular disease and cancer.

  • Cells sense force through mechanoreceptors and, regardless of the type of force applied, cells respond by exerting reciprocal actomyosin- and cytoskeleton-dependent cell-generated force by a process termed mechanoreciprocity.

  • Mechanoreciprocity maintains tensional homeostasis in the tissue and is necessary for development and tissue-specific differentiation. Its loss promotes disease progression, including liver fibrosis, atherosclerosis and cancer.

  • Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. This adaptation probably involves a combination of epigenetic chromatin remodelling events and direct physical links between the matrix and nucleus that regulate gene expression. These gene-regulatory processes are altered in diseases such as cancer.

  • Breast cancer is characterized by changes in cellular rheology and tissue level forces, a stiffening of the tissue and a progressive loss of tensional homeostasis that has been exploited to detect tumours. The mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk.

Abstract

Cells within tissues are continuously exposed to physical forces including hydrostatic pressure, shear stress, and compression and tension forces. Cells dynamically adapt to force by modifying their behaviour and remodelling their microenvironment. They also sense these forces through mechanoreceptors and respond by exerting reciprocal actomyosin- and cytoskeletal-dependent cell-generated force by a process termed 'mechanoreciprocity'. Loss of mechanoreciprocity has been shown to promote the progression of disease, including cancer. Moreover, the mechanical properties of a tissue contribute to disease progression, compromise treatment and might also alter cancer risk. Thus, the changing force that cells experience needs to be considered when trying to understand the complex nature of tumorigenesis.

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Figure 1: Cells are tuned to the materials properties of their matrix.
Figure 2: Mechanotransduction and focal adhesion maturation.
Figure 3: The normal mammary gland as a mechanically active tissue.
Figure 4: Matrix stiffness modulates cellular morphology and epidermal growth factor (EGF)-dependent growth.
Figure 5: Imaging elastography of a breast tumour.

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Acknowledgements

We apologize to the many authors whose work is not cited due to space limitations. A special thank you is extended to N. Zahir for her efforts on the text boxes, M. Paszek for his contribution to the traction force images in Fig. 1 and S. Cersosimo for administrative support. This work was supported by National Institutes of Health grant 7R01CA078731-07, Department of Defense Breast Cancer Research Era of Hope grant W81XWH-05-1-330 (BC044791), California Institute for Regenerative Medicine grant RS1-00449 and DOE grant A107165 to V.M.W., and a Sandler Family Foundation Award and National Institutes of Health grant RO3DE016868 to T.A.

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Correspondence to Valerie M. Weaver.

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DATABASES

National Cancer Institute Drug Dictionary

5-azacytidine

tamoxifen

Glossary

Rheology

The study of the deformation and flow of matter.

Viscoelasticity

Soft biological tissues can be described as viscoelastic materials. A viscous fluid resists shear flow and strain linearly with time under stress. An elastic solid undergoes deformation under stress and rapidly returns to its original state. Viscoelastic biological materials exhibit characteristics of both a viscous fluid and an elastic solid.

Endoproteinase

An enzyme that proteolytically cleaves peptides at internal amino acids.

Durotactic

Directed movement of cells up or down the stiffness gradient of a biomaterial.

Desmoplastic stroma

Stromal tissue responds to tumour cells with a characteristic desmoplasia resulting from fibroblast recruitment, collagen deposition and angiogenesis.

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Butcher, D., Alliston, T. & Weaver, V. A tense situation: forcing tumour progression. Nat Rev Cancer 9, 108–122 (2009). https://doi.org/10.1038/nrc2544

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