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Cancer invasion regulates vascular complexity in a three-dimensional biomimetic model

Pape, J; Magdeldin, T; Ali, M; Walsh, C; Lythgoe, M; Emberton, M; Cheema, U; (2019) Cancer invasion regulates vascular complexity in a three-dimensional biomimetic model. European Journal of Cancer , 119 pp. 179-193. 10.1016/j.ejca.2019.07.005. Green open access

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Abstract

Introduction There is a growing appreciation for including a complex, vascularised stroma in three-dimensional (3D) tumour models to recapitulate the native tumour microenvironment in situ. Methods Using a compartmentalised, biomimetic, 3D cancer model, comprising a central cancer mass surrounded by a vascularised stroma, we have tested the invasive capability of colorectal cancer cells. Results We show histological analysis of dense collagen I/laminin scaffolds, forming necrotic cores with cellular debris. Furthermore, cancer cells within this 3D matrix form spheroids, which is corroborated with high EpCAM expression. We validate the invasive growth of cancer cells into the stroma through quantitative image analysis and upregulation of known invasive gene markers, including metastasis associated in colon cancer 1, matrix metalloproteinase 7 and heparinase. Tumouroids containing highly invasive HCT116 cancer masses form less complex and less branched vascular networks, recapitulating ‘leaky’ vasculature associated with highly metastatic cancers. Angiogenic factors regulating this were vascular endothelial growth factor A and hepatocyte growth factor active protein. Where vascular networks were formed with less invasive cancer masses (HT29), higher expression of vascular endothelial cadherin active protein resulted in more complex and branched networks. To eliminate the cell–cell interaction between the cancer mass and stroma, we developed a three-compartment model containing an acellular ring to test the chemoattractant pull from the cancer mass. This resulted in migration of endothelial networks through the acellular ring accompanied by alignment of vascular networks at the cancer/stroma boundary. Discussion This work interrogates to the gene and protein level how cancer cells influence the development of a complex stroma, which shows to be directly influenced by the invasive capability of the cancer.

Type: Article
Title: Cancer invasion regulates vascular complexity in a three-dimensional biomimetic model
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejca.2019.07.005
Publisher version: https://doi.org/10.1016/j.ejca.2019.07.005
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Keywords: Colorectal cancer; Cancer histology; Invasion; Biomimetic; Microenvironment; Cancer stroma; Angiogenesis; Collagen
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Experimental and Translational Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Ortho and MSK Science
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Mechanical Engineering
URI: https://discovery.ucl.ac.uk/id/eprint/10080867
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