Mechanisms linking hypoxia, inflammation and chemosensitivity in feline oral squamous cell carcinoma

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The long term goal of this program is to help improve the prognosis of an important companion animal disease, feline oral squamous cell carcinoma (FOSCC). FOSCC is often resistant to chemotherapy and radiation, and complete surgical resection is not an option for many patients due to tumour size and location. FOSCC cells show activity of the inflammatory cyclooxygenase (COX) pathway. They also express a mediator of inflammation, invasion and treatment resistance called cluster of differentiation factor 147 (CD147). Tumour hypoxia (low oxygen) is a common event in many types of cancer and has been associated with treatment resistance and disease progression. This phase of the research program will test the overall hypothesis that cyclooxygenases and CD147 contribute to feline OSCC progression and chemotherapy resistance in a hypoxia-dependant manner. The first objective is to determine if hypoxia activates the COX pathway, stimulates CD147 expression, and reduces sensitivity to chemotherapy. Genetic manipulation of CD147 and the PGE2 synthesis pathway will be employed. Key mediators identified in the in vitro experiments will be examined in the mouse model using cell lines from the genetic experiments, with and without chemotherapy. In the second objective, intracellular signalling pathways serving as a mechanistic link between hypoxia, inflammation and tumour progression will be identified. This objective will also include evaluating the significance of PGE2 receptors to FOSCC behaviour. The hypothesis is that the Pi3K/AKT signalling pathway, known to be activated by PGE2 receptor EP-4, as well as during periods of hypoxia and oxidative stress, will be required for hypoxia-induced responses in feline OSCC cells. Contributions of the receptors and signalling pathways to in vitro and in vivo chemoresistance will also be determined. The third objective is to determine if anti-inflammatory drugs and bioactive phytochemical extracts from Vaccinium berries (lowbush blueberry and cranberry) can increase chemosensitivity in feline OSCC cells. It is hypothesized that the anti-inflammatory and anti-oxidant properties of the berry extracts will improve FOSCC response to chemotherapy. Eventually, the long term goal is to develop clinical trials in cats. Although this program focuses on feline OSCC, the fundamental mechanisms that are revealed will have relevance to a variety of cancers associated with inflammation (such as cancer of the gastrointestinal tract and urinary bladder). Discovering novel inflammation-associated targets will also have relevance to non-cancerous conditions that are treated with long-term anti-inflammatory drugs, such as degenerative joint disease. Finally, this research program will provide ongoing opportunities to train future scientists in the field of animal health.