Being the most aggressive human skin cancers, melanoma has always occurred with a poor prognosis. It is responsible for 80% of skin cancer. Treatments for melanoma include surgical removal, and radio- and chemotherapy, which are not effective toward the advanced stages of the disease. Only three chemotherapy drugs, hydroxyurea, dacarbazine and interleukin-2, are currently approved by the Food and Drug Administration for metastatic melanoma, and the therapeutic response rate is only 5%-20%. Thus, there is a need for novel therapies that can target tumours, especially when the tumour cells become refractory to chemotherapy. ELR–CXC chemokines with a Glutamine – leucine – arginine (ELR) motif (for example, interleukin-8/CXCL8) are able to chemoattract neutrophils during inflammation responses via their receptors, CXCR1 and CXCR2, which can be expressed by human malignant tumour cells, keratinocytes, endothelial cells, and fibroblasts. CXCR1 and CXCR2 play very important roles in melanoma by promoting tumour cell proliferation, angiogenesis, and metastasis. They are also involved in the tumour’s becoming refractory to chemotherapy. An ELR–CXC chemokine antagonist developed by our lab, CXCL8(3-72)K11R/G31P (G31P), effectively blocks CXCR1- and CXCR2- induced inflammatory responses, and further antagonizes the functions of heterologous G protein–coupled receptor’s (GPCR). The tumour–associated GPCRs, along with ELR–CXC chemokines and their receptors, have been shown to simultaneously increase in several tumour models, including melanoma. Thus, given the knowledge regarding the importance of the ELR-CXC chemokines and heterologous GPCRs’ in melanoma and G31P’s ability to block ELR-CXC chemokines and at least some heterologous GPCRs, we hypothesize that G31P is a viable therapeutic option for melanoma cancers by virtue of its success in blocking tumour progression in mouse models. Our data indicated that ELR-CXC chemokine antagonism with G31P had no significant impact on tumour growth or tumour-induced angiogenesis, which suggested that blockade of CXCR1 and CXCR2 alone was insufficient to block tumour development in this melanoma mouse model. Evaluation of other tumour-related parameters (e.g., angiogenic patterns and stress protein level) are recommended as a means of determining what parameters beyond CXCR1 and CXCR2 signaling are important in tumour progression in our matrigel model.

Endometriosis, characterized by the growth of endometrium outside the uterine cavity, is a disease which causes pelvic pain, inflammation and associated with infertility. Endometrium, which exits the uterus through retrograde menstruation, must establish a new blood supply as it attaches and invades into ectopic tissues to form an endometriosis lesion. Angiogenesis is therefore essential in endometriosis disease progression. The inhibition of blood vessel growth by anti-angiogenic agents is a potential strategy to manage endometriosis disease progression. This thesis investigated angiogenesis of endometriosis lesions, and evaluated a novel anti-angiogenic peptide as a potential therapeutic to manage endometriosis. An atlas on the microscopic anatomy of the pregnant mouse uterus is also presented. Synuclein-γ (SNCG), a protein involved in cellular proliferation, was found to have elevated expression in endothelial cells of endometriosis tissue compared to eutopic endometrium. In an alymphoid xenograft mouse model of human endometriosis, where human endometrium is engrafted into the peritoneal cavity of Rag2-/-/IL2r-/- female mice, peptide inhibition of SNCG resulted in reduced vascularization of endometriotic lesions. This study indicates that SNCG has a potential role in angiogenesis of endometriosis lesions. Using the same alymphoid mouse model, we evaluated the effect of an anti-angiogenic thrombospondin-1 mimetic peptide, ABT-898, on angiogenesis of endometriotic lesions. ABT-898 inhibited endothelial cell proliferation and tube formation in vitro. Mice treated with ABT-898 showed reduced vascularity of endometriosis lesions compared with control. Angiogenesis is also an essential process in the female reproductive system. Females with endometriosis are of reproductive age, so it is essential to establish that anti-angiogenic therapies do not iii interfere with reproduction. We evaluated the effect of ABT-898 on angiogenesis in the female reproductive tract in non-pregnant mice. ABT-898 did not affect estrous cyclicity, or vascularity of the uterus or ovary in non-pregnant animals. ABT-898 did not alter litter size or pup weight when given to pregnant mice throughout gestation. In summary this thesis implicated a role for SNCG in angiogenesis of endometriosis lesions, and found that ABT-898 could be a useful therapeutic to manage endometriosis disease progression as it reduces angiogenesis of endometriotic lesions, while having no observable effect in reproductive organs. / Thesis (Ph.D, Anatomy & Cell Biology) -- Queen's University, 2014-05-01 14:42:32.655

No description available.

No description available.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 4 uppsatser.

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