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Transglutaminase-2 Mediates the Biomechanical Properties of the Colorectal Cancer Tissue Microenvironment that Contribute to Disease Progression

1
School of Engineering and Materials Science, Queen Mary University of London, London E1 4NS, UK
2
Biomolecular Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK
3
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK
4
Department of Surgery, Southampton University Hospital NHS Trust, Southampton SO16 6YD, UK
5
Laboratory for Optical and Computational Instrumentation, University of Wisconsin at Madison, Madison, WI 53706, USA
*
Author to whom correspondence should be addressed.
These authors share equal contribution.
Cancers 2019, 11(5), 701; https://doi.org/10.3390/cancers11050701
Received: 18 March 2019 / Revised: 4 May 2019 / Accepted: 16 May 2019 / Published: 21 May 2019
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Abstract

Colorectal cancer is the third most common cancer worldwide, and the fourth leading cause of malignancy-related mortality. This highlights the need to understand the processes driving this disease in order to develop new treatments and improve patient outcomes. A potential therapeutic target is the increased stiffness of the tumour microenvironment, which is linked to aggressive cancer cell behaviour by enhancing biomechanical signalling. In this study, we used an siRNA-based approach to investigate the contribution of the protein cross-linking enzyme transglutaminase-2 (TG2) to matrix remodelling and biomechanical properties of the tumour microenvironment. TG2 inhibited cancer cell growth in organotypic 3D fibroblast/SW480 co-culture models, and biomechanical analysis demonstrated that colorectal cancer cells induced fibroblast-mediated stiffness which was inhibited by silencing TG2. These biomechanical changes were associated with observed alterations to collagen fibre structure, notably fibre thickness. Our in vitro findings of collagen composition changes were also seen with imaging biopsied tissues from patients with colorectal cancer, with TG2 correlating positively with thicker collagen fibres, and associating with poor outcome as determined by disease recurrence post-surgery and overall survival. In conclusion, this study demonstrates a role for TG2 in the stromal response to invading tumour, leading to tissue stiffening and poor outcome in patients. View Full-Text
Keywords: colorectal; transglutaminase; remodelling; biomechanics; collagen; extracellular matrix; tumor microenvironment colorectal; transglutaminase; remodelling; biomechanics; collagen; extracellular matrix; tumor microenvironment
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Delaine-Smith, R.; Wright, N.; Hanley, C.; Hanwell, R.; Bhome, R.; Bullock, M.; Drifka, C.; Eliceiri, K.; Thomas, G.; Knight, M.; Mirnezami, A.; Peake, N. Transglutaminase-2 Mediates the Biomechanical Properties of the Colorectal Cancer Tissue Microenvironment that Contribute to Disease Progression. Cancers 2019, 11, 701.

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