Pape, Judith Maria;
(2020)
Development of a 3D Biomimetic Tissue-Engineered Model of Cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Introduction: Three dimensional (3D) models of cancer have been a major focus in advances to research discoveries toward cancer progression and the involvement of the cancer stroma. Next to extracellular matrix components such as hyaluronic acid (HA), cancer associated fibroblasts (CAFs) are highly differentiated and heterogenous cancer stromal cells that promote tumour growth, angiogenesis and matrix remodelling. Methods: We utilised a novel 3D in vitro model of colorectal (CRC) and pancreatic cancer, composed of an artificial cancer mass (ACM) with varying invasive propensities and a stromal compartment. We incorporated extracellular matrix components and six colorectal patient-derived CAF samples to study their differential effects. The chemotherapy drug paclitaxel was tested on 3D models of pancreatic cancer with increasing complexity. Results: The main finding was that the invasive nature of a cancer mass directly influenced the complexity of a developing vascular network. All network alignments were quantified and endothelial structures aligned along the chemotactic gradient formed by the CRC mass. CRC and pancreatic cancer invades as clusters and sheets in contrast to their non-cancerous counterparts. Using quantitative PCR, we demonstrated the key genes and active proteins responsible for this invasion. The addition of stromal fibroblasts and endothelial cells provided a biomimetic microenvironment which was reflected by the upregulation of invasive genes. CAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. Pancreatic cancer cells within a highly complex 3D model responded to paclitaxel and dose response curves could be established. Conclusion: These results support, within a biomimetic 3D, in vitro framework, the underlying gene pathways involved in cancer invasion and vascularisation. Furthermore, a complex model of pancreatic cancer was developed accounting for the large stromal proportion and used as a drug testing platform.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Development of a 3D Biomimetic Tissue-Engineered Model of Cancer |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices 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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10086916 |
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