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Fes was first discovered as a protein-tyrosine kinase-encoded by the v-fes retroviral oncogene. Retrovirally encoded Fes oncoproteins induced tumors in chickens and cats and cause tumors in transgenic mice; however, a role for Fes in human cancer has not been established. This thesis identifies tumor promoting roles of Fes through effects on stromal cells using genetic mouse models. First, in an orthotopic mouse mammary gland engraftment model, I found that loss of Fes in the host correlated with reductions in engrafted tumor growth rates, metastasis and circulating tumor cells, which may be partly due to reduced vascularity and fewer tumor-associated macrophages. We also showed Fes-deficient macrophages were less capable of promoting tumor cell invasion in co-culture experiments. Next, I observed delayed tumor onset in the absence of Fes in a transgenic mouse model of breast cancer driven by an activated HER2/Neu allele. This longer tumor latency correlated with hyperinflammatory status of Fes-deficient normal mammary glands. Taken together, these observations argue that Fes inhibition might provide therapeutic benefits in breast cancer, by attenuating tumor-associated angiogenesis and the metastasis-promoting functions of tumor-associated macrophages, or by delaying breast tumor onset in women with HER2 overexpression. Finally, we showed that mice engrafted with IL-4 producing tumor cells developed tumors with significantly reduced growth rates and a complete attenuation of lung metastasis, which correlated with increased numbers of macrophages and enhanced phagocytic capability of macrophages in the tumor microenvironment. These observations suggest that IL-4 could be a good candidate for immunotherapy. / Thesis (Ph.D, Pathology & Molecular Medicine) -- Queen's University, 2013-12-18 11:44:40.294

Since mammalian target of rapamycin (mTOR) and N-myristoltransferase (NMT) have been shown to be potentially related to breast cancer, mTOR-NMT signalling pathway is taken into specific consideration. In this thesis, mathematical models are developed to not only describe the mTORNMT signalling pathways, but also to analyze and predict the response to a treatment. Based on different biological hypotheses, candidate models are obtained by using an ordinary differential equation formalism. An optimization method called the Differential Evolution algorithm is applied to find the best parameter sets for our candidates. Doing so, will give the smallest distance between experimental data and simulated results. The experimental data are provided by Dr Shrivastav’s laboratory, Department of Biology, University of Winnipeg. Furthermore, the mathematical analysis for our candidate models has been found to show their asymptotic behaviours.To determine which candidate model is most likely to be the ”best” among the subgroup of models, model selection is used. Ultimately, the collaboration with Dr Shrivastav’s laboratory let us understand the simplified mTOR-NMT signalling pathway. / October 2016

The chalcone motif is a privileged structure present in an extensive range of biologically active molecules. The chalcone structure can also serve as a versatile starting material for more complex molecules in medicinal chemistry. Eleutherobin, isolated from the Australian coral Eleutherobia and sarcodictyin, isolated from the Mediterranean coral Sarcodictyon roseum are natural products displaying nanomolar cytotoxicity against a range of cancer cell lines including Taxol®-resistant cell lines. Both natural products act as microtubule stabilising agents and will be valuable additions to the clinic, however their limited availability and lengthy total syntheses prevent further development. The urocanic ester side chain present in eleutherobin and sarcodictyin was identified as being critical for biological activity. We discuss the design, synthesis and biological evaluation of fourteen chalcone analogues based on this urocanic motif with the lead chalcone displaying promising antiproliferative activity in a range of cancer cell lines. Combretastatin A-4 is a promising microtubule destabiliser under clinical development. The Z configuration is vital for biological activity, however it can isomerise to the inactive E configuration. We report a library of twenty pyrazolines synthesised from chalcones as “Z restricted” combretastatin analogues with the lead pyrazoline displaying potent antiproliferative activity in cancer cell lines due to the disruption of tubulin. Tissue engineering is a diverse interdisciplinary field that applies engineering principles to the biological sciences with the aim of maintaining or replacing tissue function. Recent developments have revealed metal chelation to be a valuable tool to control the architecture of tissue engineering scaffolds. We report a library of ten novel pyrazolines and their potential as metal chelators. Maltol is a well established Fe3+ chelator with a low toxicity profile. We report a novel maltol hydrazide which can be attached to the cell surface which upon addition of Fe3+ results in cellular aggregation due to metal chelation. Further studies revealed that this process can be applied to form heterocellular aggregates composed of two different cancer types with valuable applications in tissue engineering and cancer research.

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One of the principal themes of the prolific research on the subject of CMM has been to establish parameters that can predict the clinical outcome. The most useful of these prognostic parameters have been derived from histopathological studies, but none has been consistently reliable. Therefore, other parameters may be presumed to influence the clinical course and a body of evidence acquired from laboratory experimental, pathological and clinical studies suggests that host immune effector mechanisms may be relevant in this regard. Immunohistochemistry provides a means by which histopathologists can attempt to elucidate features of the interaction between tumour cells and host immune effector cells. Such an approach was adopted for the studies presented in this thesis. The T-cell infiltrate associated with CMM, although more intense than that associated with either lentigo maligna or nevocellular nevi, was qualitatively similar with regard to its immunophenotypic characteristics. Natural killer (NK) cells were, however, identified only in association with some cases of CMM. Interleukin-2 (IL-2) was localised principally within melanoma cell nuclei, the uptake of IL-2 by melanoma cells presumably being mediated by the β-chain of the IL-2 receptor which was selectively expressed by tumour cells. Contrary to most previous studies, expression of ICAM-1 and LFA-3 by melanoma and nevus cells was ubiquitous. Expression of these molecules therefore seems unlikely to aid the differential diagnosis of melanocytic lesions and is of doubtful independent prognostic significance. The role that these molecules may have in facilitating host immune responses against tumour cells is unclear; expression of these molecules correlated with neither the intensity of the host inflammatory cell infiltrate nor the presence of regression.

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