The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Transglutaminase-2 mediates the biomechanical properties of the colorectal cancer tissue microenvironment that contribute to disease progression

Transglutaminase-2 mediates the biomechanical properties of the colorectal cancer tissue microenvironment that contribute to disease progression
Transglutaminase-2 mediates the biomechanical properties of the colorectal cancer tissue microenvironment that contribute to disease progression
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
2072-6694
Delaine-Smith, Robin
f0ac3574-031f-435a-97d5-c2308e60e61c
Wright, Nicola
14f142fd-f0e6-4508-a1ae-b67c73883d38
Hanley, Chris
7e2d840d-e724-4389-a362-83741ccdf241
Hanwell, Rebecca
756f8c15-ae6d-4be5-89f8-77180bb506a8
Bhome, Rahul
d7b1e0d3-5925-460a-871d-5f52f69c649b
Bullock, Marc
e060d2b2-5e6f-449b-b8ae-f411b5a396c2
Drifka, Cole
b167e5bb-3311-4606-833b-3948d5bd4c55
Eliceiri, Kevin W.
d845752d-c745-4360-b046-8149371ae2d3
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Knight, Martin
a3707416-0369-4878-959a-02b09641dd3e
Mirnezami, Alexander
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Peake, Nicholas
792407fa-55e4-4a2d-a32e-59a3429f7115
Delaine-Smith, Robin
f0ac3574-031f-435a-97d5-c2308e60e61c
Wright, Nicola
14f142fd-f0e6-4508-a1ae-b67c73883d38
Hanley, Chris
7e2d840d-e724-4389-a362-83741ccdf241
Hanwell, Rebecca
756f8c15-ae6d-4be5-89f8-77180bb506a8
Bhome, Rahul
d7b1e0d3-5925-460a-871d-5f52f69c649b
Bullock, Marc
e060d2b2-5e6f-449b-b8ae-f411b5a396c2
Drifka, Cole
b167e5bb-3311-4606-833b-3948d5bd4c55
Eliceiri, Kevin W.
d845752d-c745-4360-b046-8149371ae2d3
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Knight, Martin
a3707416-0369-4878-959a-02b09641dd3e
Mirnezami, Alexander
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Peake, Nicholas
792407fa-55e4-4a2d-a32e-59a3429f7115

Delaine-Smith, Robin, Wright, Nicola, Hanley, Chris, Hanwell, Rebecca, Bhome, Rahul, Bullock, Marc, Drifka, Cole, Eliceiri, Kevin W., Thomas, Gareth, Knight, Martin, Mirnezami, Alexander and Peake, Nicholas (2019) Transglutaminase-2 mediates the biomechanical properties of the colorectal cancer tissue microenvironment that contribute to disease progression. Cancers, 11 (5), [E701]. (doi:10.3390/cancers11050701).

Record type: Article

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

Text
cancers-11-00701 - Version of Record
Available under License Creative Commons Attribution.
Download (5MB)

More information

Accepted/In Press date: 16 May 2019
Published date: 21 May 2019

Identifiers

Local EPrints ID: 432411
URI: http://eprints.soton.ac.uk/id/eprint/432411
ISSN: 2072-6694
PURE UUID: 3fd5a218-42bc-428c-a220-35a3b72cc155
ORCID for Chris Hanley: ORCID iD orcid.org/0000-0003-3816-7220

Catalogue record

Date deposited: 12 Jul 2019 16:30
Last modified: 26 Nov 2021 03:03

Export record

Altmetrics

Contributors

Author: Robin Delaine-Smith
Author: Nicola Wright
Author: Chris Hanley ORCID iD
Author: Rebecca Hanwell
Author: Rahul Bhome
Author: Marc Bullock
Author: Cole Drifka
Author: Kevin W. Eliceiri
Author: Gareth Thomas
Author: Martin Knight
Author: Nicholas Peake

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×