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Title: Role of semaphorin 3A in osteosarcoma
Author: de Ridder, D.
ISNI:       0000 0004 7431 1362
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2018
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Osteosarcoma is the most prevalent malignant primary bone tumour and mainly affects children and adolescents. Since the introduction of chemotherapy the survival rate for osteosarcoma patients has not improved, implicating the need for new therapeutic targets. Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, is essential for bone metabolism and plays an important role in the regulation of tumorigenesis and metastasis, but its function in osteosarcoma remains unknown. The aim of this thesis was to study the effects of human recombinant Sema3A and Sema3A overexpression on tumour growth, metastasis, osteosarcoma-associated bone damage and ectopic bone formation in preclinical models of human osteosarcoma. Exposure to recombinant Sema3A enhanced alkaline phosphatase activity in a panel of osteosarcoma cell lines and inhibited their migration without affecting cell viability in vitro. Administration of exogenous Sema3A in mice increased bone volume in the healthy and osteosarcoma-bearing legs these effects were accompanied with a trend towards more osteoblasts and less osteoclasts. Sema3A overexpression reduced viability, migration and invasion of KHOS cells in vitro however, both overexpression and administration of recombinant Sema3A had no effect on tumour growth. Surprisingly, overexpression of Sema3A reduced ectopic bone formation. Continuous exposure of osteoblasts to conditioned medium from Sema3A overexpressing cells inhibited mineralization and Wnt/ß-catenin signalling without affecting osteoblast viability. This effect may be partially explained by the upregulated expression of DKK1 in Sema3A overexpressing KHOS cells. In conclusion, these studies suggest that Sema3A acts as a tumour inhibitor on osteosarcoma in vitro. Administration of recombinant Sema3A partially protected the bone from osteosarcoma-associated osteolysis. In contrast, Sema3A overexpression reduced osteosarcoma-associated ectopic bone formation in mice. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma-associated bone damage. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term use as therapeutic agent in osteolytic bone diseases.
Supervisor: Idris, A. I. I. ; Heymann, D. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available