Review Article The emergence of solid stress as a potent biomechanical marker of tumour progression Alain Vella, Enanga M. Eko and Armando del Río Hernández Department of Bioengineering, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K. Correspondence: Alain Vella (alain.vella@imperial.ac.uk) Cancer is a disease of dysregulated mechanics which alters cell behaviour, compromises tissue structure, and promotes tumour growth and metastasis. In the context of tumour progression, the most widely studied of biomechanical markers is matrix stiffness as tumour tissue is typically stiffer than healthy tissue. However, solid stress has recently been identified as another marker of tumour growth, with findings strongly suggesting that its role in cancer is distinct from that of stiffness. Owing to the relative infancy of the field which draws from diverse disciplines, a comprehensive knowledge of the relation- ships between solid stress, tumorigenesis, and metastasis is likely to provide new and valuable insights. In this review, we discuss the micro- and macro-scale biomechanical interactions that give rise to solid stresses, and also examine the techniques developed to quantify solid stress within the tumour environment. Moreover, by reviewing the effects of solid stress on tissues, cancer and stromal cells, and signalling pathways, we also detail its mode of action at each level of the cancer cascade. Biomechanics: another facet of the tumour milieu On the timeline of science, a century is but a blip. And yet, the astounding advances made in cancer research over the last 100 years have made oncology one of the most exciting fields in biomedicine. The history of cancer research suggests that, to date, the primary focus has been on the biochemical underpinnings of cancer. While the significance of such research is unequivocal, all living beings are also governed by principles extrinsic to biochemistry. The laws of physics have indeed been applied to the biological domain ever since the time of Aristotle who related biomechanics to phenomena as diverse as the motion of animals’ bodies to peristalsis. Apart from playing a vital role in physiological functions, biomechanics are also at the heart of many pathologies including, but not limited to, car- diomyopathy [1], atherosclerosis [2], osteoarthritis [3], degenerative vascular disease [4], cataracts [5], and cancer [6]. In a biomechanics context, the tumour mechanical milieu differs markedly from that of healthy tissue. Indeed, one observes that the extracellular matrix (ECM) in the tumour microenvironment is typically stiffer than normal tissue [7–9]. This is especially true of breast and pancreatic tumours which, presenting a dense and cross-linked ECM, are characterised by a strong desmoplastic reaction [10]. This increased stiffness has been shown to activate cell surface integrins which, in turn, up-regulates ECM stiffness and initiates a positive feedback loop which promotes the malignant phenotype in epithelial cells [11]. Recently, results from our laboratory have also shown increased matrix stiffness to promote epithelial-to-mesenchymal (EMT) transition in cancer cells [10], and cancer cell stiffness has been strongly associated with invasiveness [12]. While studies investigating the effect of stiffness on tumour progression currently constitute the bulk of cancer biomechanics research, another mechanical cue, solid stress, has recently emerged as a key marker of solid tumour growth. Solid stress, which is negligible in most healthy tissues, develops within the tumour microenvironment as cancer and stromal cells proliferate, and ECM deposition increases [13–18]. Key to note is that while stiffness (E) is an inherent material property which Version of Record published: 21 December 2018 Received: 15 August 2018 Revised: 2 November 2018 Accepted: 6 November 2018 © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society and the Royal Society of Biology 739 Emerging Topics in Life Sciences (2018) 2 739–749 https://doi.org/10.1042/ETLS20180049