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Molecular Determinants of Malignancy in Canine Osteosarcoma

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Title: Molecular Determinants of Malignancy in Canine Osteosarcoma
Author: Larsen, Dana Meegan
Department: Department of Pathobiology
Program: Veterinary Science
Advisor: Wood, Geoffrey A.
Abstract: Cancer is essentially a genetic disease of uncontrolled cell survival and proliferation. Medical therapy has traditionally involved chemotherapy and radiation which inhibit the replication of actively dividing cells in a fairly non-selective manner. Research into the molecular pathogenesis of cancer has enabled the recent development of therapy targeted to receptors or signaling pathways crucial to the development and progression of specific cancers and revealed molecular markers that can be used to predict prognosis and treatment response. The work presented in this thesis examines the expression of two potential molecular markers of malignancy, the R1alpha regulatory subunit of cyclic AMP-dependent protein kinase A (PRKAR1A) and insulin-like growth factor 2 (IGF2) retrospectively in a population of canine osteosarcoma patients. Furthermore, it describes the derivation and preliminary characterization of canine osteosarcoma primary cell cultures and the use of these cells to assess the effects of PRKAR1A expression on sensitivity to chemotherapeutic drug treatment in vitro. Post-chemotherapy overall survival was significantly longer in canine osteosarcoma patients with tumours expressing low levels of PRKAR1A, and PRKAR1A expression did not correlate with mitotic index. IGF2 expression was generally high in the small numbers of cases examined, did not differ between axial and appendicular sites and did not correlate with either mitotic index or survival. PRKAR1A expression varied between cell cultures, but did not appear to be related to expression levels of phosphorylated cAMP response element-binding (phospho- CREB), a downstream target of cyclic AMP (cAMP)-dependent protein kinase A (PKA). In vitro chemosensitivity did not correlate with PRKAR1A expression, but faster growing cells with shorter doubling times and higher rates of BrdU incorporation tended to be more chemosensitive. In summary, this work identifies an association between low tumour PRKAR1A expression and prolonged post-chemotherapy survival in dogs with osteosarcoma and provides preliminary evidence suggesting that this survival advantage may not be associated with downstream phosphorylation of CREB or sensitivity of the tumour cells to chemotherapeutic agents.
Date: 2011-11
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