A bioengineer discusses how mechanical forces in tissues may promote malignancy.

The connective-tissue protein collagen has been considered to be a structural barrier against tumour invasion in tissues. Enzymes that cleave collagen and other extracellular matrix (ECM) molecules were thus thought to promote tumour progression, but inhibitors of these enzymes have failed in clinical trials. And paradoxically, increased collagen expression is associated with a greater incidence of cancer spread.

Working with mice, Valerie Weaver of the University of California, San Francisco, and her team show that other ECM-remodelling parameters regulate malignancy (K. R. Levental et al. Cell 139, 891–906; 2009). They studied an enzyme that initiates collagen crosslinking and is often found in tissue around tumours. They reveal that the crosslinking increases the stiffness of collagen matrices, which upregulates growth-factor signalling and breast malignancy. This suggests that tumour progression depends on a tissue-remodelling process that is regulated by biochemical and mechanical factors.

Bioengineers developing implantable materials that promote tissue regeneration can also learn a lot from this paper. Dense collagen capsules typically form around implanted biomaterials, which has prompted a search for clues to how to engineer surfaces that promote blood-vessel formation and tissue regeneration rather than scarring.

Knowing which factors promote malignancy may also help us to engineer materials and tissues that tip the balance towards enhanced tissue regeneration. This paper might thus stimulate ideas on how to interfere with the interplay between ECM-crosslinking enzymes that enhance matrix stiffness and ECM-protein-cleaving enzymes. Doing so may affect mechanosensitive cell-signalling pathways, promoting regeneration.

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