Papadaki, V; (2014) Roles of the Small Leucine-rich Repeat Proteoglycans OMD and PRELP in Development and Cancer. Doctoral thesis , UCL (University College London).

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Abstract

Osteomodulin (OMD) and Proline/arginine-rich and Leucine-rich Repeat protein (PRELP) belong to the small leucine-rich repeat proteoglycan (SLRP) family and as extracellular matrix components have the ability to influence various cellular functions, including cell growth, migration and proliferation, while their mutation or aberrant expression can cause developmental disorders and cancer. This thesis extends previous work in further understanding the roles of OMD and PRELP in cancer and also during mouse development. In the current project OMD and PRELP are overexpressed in a bladder cancer cell line where they are found to alter cell morphology, reduce cell invasion and anchorage-independent growth, while they also inhibit tumour growth in xenograft mouse models. Additionally, we show that OMD and PRELP mediate their effects by cross-regulating different signalling pathways and also by affecting tight junction formation. Furthermore, novel knock-out mouse models of OMD and PRELP were generated, where a Lac-Z cassette has been inserted in the coding regions of the two genes, allowing us to follow their expression under X-gal staining. Therefore a detailed analysis of expression patterns was initially conducted. OMD and PRELP were both expressed in skeletal elements during mouse development, while in adult mice they were differentially expressed in neurons and epithelia of the brain and the eye, and in the urothelium of the bladder. Finally, the novel knock-out mice were used to assess any cancer-related aberrant phenotypes arising from OMD and PRELP deficiency. The bladders of the knock-out mice presented with early stages of urothelial papillary formations, where the junctional complexes were also disrupted, suggesting that lack of OMD and/or PRELP is permissive for cancer initiation. Overall, with our current findings we hope to improve the understanding of SLRP biology in carcinogenesis, and we would like to propose OMD and PRELP as potential targets for the development of cancer therapies.

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