The influence of aspects of the biophysical environment on ovarian cancer cell behaviour
|dc.contributor.author||Sarwar, Mian Makhdoom|
|dc.identifier.citation||Sarwar, M. M. (2020). The influence of aspects of the biophysical environment on ovarian cancer cell behaviour (Thesis, Doctor of Philosophy). University of Otago. Retrieved from http://hdl.handle.net/10523/9887||en|
|dc.description.abstract||It has been increasingly acknowledged that the extracellular physical environment plays a vital role in cancer development and progression. However, the precise mechanisms of how the biophysical extracellular environment regulates the cancer cell responses is still not known. Here, the effects of the biophysical extracellular environment on fundamental aspects of cancer cell behaviour were studied using cell culture models. A bioimprint cell culture model was developed in our laboratory to provide substrates with cell-like topographical features in order to decipher cellular responses specifically associated with the biophysical environment. The cells were cultured on substrates of two different topographies, a negative replica (concave) and a positive replica (convex) of a monolayer of cells, and also on a flat substrate. Three ovarian cancer cell lines representing distinct ovarian cancer subtypes were investigated. Thus, the cells were cultured in a similar biochemical milieu but in three distinct physical environments, and cell behaviour including cell morphology, protein expression, proliferation and chemosensitivity were investigated. The results from this work demonstrated that substrate bioimprinted topography negatively regulated cell spreading, whereas it positively upregulated fibrillar protrusion numbers. Results also implicated topography-mediated increased focal adhesion and Rho signalling that was associated with the upregulated growth observed on the bioimprinted substrates. One of the important findings from this study was the reduced chemosensitivity on the bioimprinted substrates, compared to cells on the flat substrate, particularly to carboplatin rather than to paclitaxel. Inhibition of focal adhesion signalling restored platinum sensitivity on the bioimprinted substrates. Later experiments indicated the involvement of upregulated mitogen-activated protein kinase (MAPK) pathway in the altered drug sensitivities. Thus, the work using bioimprinted substrates highlighted the importance of biophysical environment in cancer cell behaviour. With the thought that collagen is a dominant matrisomal protein, and is an important element in the framework of the extracellular environment, the collagen morphology in commercially obtained normal and cancerous ovarian tissue was investigated. A histochemical study revealed the presence of homogenously abundant thin collagen fibrils in the normal ovarian tissue, in contrast to less abundant, heterogeneously thick collagen fibres in the cancerous ovarian tissue. This altered collagen architecture may provide biophysical signals distinct from those provided by the normal collagen fibrils and thereby regulate tumour progression via mechanotransduction-associated pathways. Furthermore, ovarian tumour tissues displayed higher expression of p-FAK and p190RhoGEF, suggesting there was upregulated focal adhesion and Rho/ROCK signalling in ovarian tumours, especially in high-grade tumours. To add further information to the notion that, as an element of the biophysical extracellular environment, collagen architecture modulates disease progression, the behaviour of ovarian cancer cells cultured in four different collagen gels was investigated. A model in which cells were cultured in disrupted collagen was developed. Collagen architecture was altered using matrix metalloproteinase (MMP1). The disrupted collagen cell culture model provided 3D biomechanical cues to the encapsulated ovarian cancer cells. The results from this work supported the speculation that collagen architecture influences ovarian cancer cell proliferation. Also, growth responses to the inhibition of focal adhesion and Rho signalling was altered, which indicated the involvement of these pathways in the biomechanical modulation of cell growth associated with collagen architecture. Further, the findings from this work indicated that collagen disruption reduced sensitivity to carboplatin, whereas paclitaxel sensitivity was not significantly affected. This is consistent with the significantly reduced carboplatin sensitivity on the bioimprinted substrates. This implies that biophysical modulation of chemosensitivity is a selective process. Thus, the study provided evidence that the biophysical environment modulates ovarian cancer cell responses.|
|dc.publisher||University of Otago|
|dc.rights||All items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.|
|dc.title||The influence of aspects of the biophysical environment on ovarian cancer cell behaviour|
|thesis.degree.discipline||Obstetrics and Gynaecology- UOC|
|thesis.degree.name||Doctor of Philosophy|
|thesis.degree.grantor||University of Otago|
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