Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / "The present study investigated the expression and function of IGF-1R, CXCR4 and CCR7, in metastatic MDA-MB-231 and non-metastatic MCF-7 cells." / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1295746 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / This thesis describes two studies, one in vitro and one in vivo, which show that Apo2L/TRAIL can prevent breast cancer-induced bone destruction, and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. They also highlight the complexity of Apo2L/TRAIL signalling, and the need for further studies into this area to fully exploit the potential of Apo2L/TRAIL as an anti-cancer agent for breast and other cancers. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1283688 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / This thesis describes two studies, one in vitro and one in vivo, which show that Apo2L/TRAIL can prevent breast cancer-induced bone destruction, and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. They also highlight the complexity of Apo2L/TRAIL signalling, and the need for further studies into this area to fully exploit the potential of Apo2L/TRAIL as an anti-cancer agent for breast and other cancers. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1283688 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / Metastasis is a multi-step process during which cancer cells disseminate from the primary tumour and establish secondary tumours in distant sites. The mechanisms for organ-specific metastasis are poorly understood, although recent findings suggest the role of a number of chemokine receptors on various cancer cells such as breast CXCR4 as well as CCR7, are a protein-coupled chemokine receptor (apCR) that have proven to be of considerable biological significance, since their expression has been shown on various malignant breast cancer cell lines, tumours and metastases. In this study the expression and function of CXCR4 and CCR7 was examined in a range of human breast cancer cell lines covering a spectrum of malignant and non-malignant phenotypes. The data revealed that while surface levels of CXCR4 and CCR7 were uniform across the entire panel of breast cancer cell lines, only highly invasive cells, metastatic in immunocompromised mice, expressed functional chemokine receptors. Moreover, multiple signalling pathways downstream of a proteins in the highly invasive cells were found to be activated however chemokine treatment failed to activate any of the downstream kinase cascades examined in non-invasive cell lines. For the first time, to the best of our knowledge, chemokine receptor function was demonstrated to be subject to complex and tightly-controlled regulation in epithelial breast cancer cells via differential a protein-receptor complex formation and that this regulation might significantly contribute to the transition from non-metastatic to malignant tumours. Finally, the role of CXCR4 and CCR7 during breast cancer metastasis was verified using a humanised breast cancer metastasis mouse modeL By modulating the expression of chemokine receptors using siRNA-mediated knockdown, metastasis of breast cancer cells to the lungs of SCID mice was dramatically inhibited. In summary, the data point to distinct molecular mechanisms of chemokine receptor activation used by transformed invasive breast epithelial cells which leads to the metastatic spread of these cancer cells to distant sites. Improved understanding of the role of chemokine receptor/ligand interaction in metastasis may lead to novel approaches in the treatment and management of breast cancer as well as other solid tumour malignancies. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1289342 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

In the UK, 12,000 patients die from metastatic breast cancer annually. There is therefore an urgent need to identify the molecules that cause metastasis. Recent work has revealed a role for the RUNX family of transcription factors in the development of metastatic breast cancer. The RUNX proteins form active transcription factor complexes when bound by the heterodimeric partner CBFβ to regulate the expression of metastatic genes. Previous work from our laboratory has demonstrated that knockdown of CBFβ resulted in a decreased invasion capacity of the metastatic breast cancer cell line MDA-MB-231. Three-dimensional culture of MDA-MB-231 cells revealed that loss of CBFβ induces a mesenchymal to epithelial transition (MET). The aim of this project was to determine the role of the RUNX/CBFβ complex in maintaining the mesenchymal phenotype of metastatic breast cancer cells. The data presented show that the phenotype changes were accompanied by changes in EMT marker-gene expression, including Snai2, MMP9, and MMP13. Induction of CBFβ in the CBFβ-knockdown cells remarkably restored both the invasive capacity and the mesenchymal phenotype. Further analysis revealed that maintenance of the mesenchymal phenotype was dependent upon both CBFβ-partner proteins, RUNX1 and RUNX2. Taken together the data presented in this thesis demonstrate that RUNX/CBFβ complexes drive the epithelial to mesenchymal transition (EMT) in breast cancer cells. These findings are likely to be important in the development of potential therapies to inhibit the metastatic spread of breast cancer.

No / Breast cancer is one of the most prevalent malignancies worldwide. It consists of a group of tumor cells that have the ability to grow uncontrollably, overcome replicative senescence (tumor progression) and metastasize within the body. Metastases are processes that consist of an array of complex gene dysregulation events. Although these processes are still not fully understood, the dysregulation of a number of key proteins must take place if the tumor cells are to disseminate and metastasize. It is now widely accepted that future effective and innovative treatments of cancer metastasis will have to encompass all the major components of malignant transformation. For this reason, much research is now being carried out into the mechanisms that govern the malignant transformation processes. Recent research has identified key genes involved in the development of metastases, as well as their mechanisms of action. A detailed understanding of the encoded proteins and their interrelationship generates the possibility of developing novel therapeutic approaches. This review will focus on a select group of proteins, often deregulated in breast cancer metastasis, which have shown therapeutic promise, notably, EMT, E-cadherin, Osteopontin, PEA3, Transforming Growth Factor Beta (TGF-β) and Ran.

Current treatment for spinal metastasis involves a multimodal approach, including bisphosphonates and radiation therapy. Yet, tumour response varies considerably, thus novel treatments or combination therapies are needed to treat these metastases while preserving stability and integrity of the spinal column. Photodynamic therapy (PDT) has been shown to be successful in destroying vertebral osteolytic tumours and enhancing vertebral structure, particularly in combination with bisphosphonates. This thesis aims to evaluate the longer-term effects of PDT alone and in combination with bisphosphonate or radiation therapy on healthy vertebrae, and the short-term effects of PDT combined with radiation therapy on healthy and metastatically-involved vertebrae. The benefits of PDT on vertebral structure, both at short-term and longer-term time-points, were greatest in combination with previous bisphosphonate therapy. Similar effects, to a lesser magnitude, were seen with PDT in combination with radiation therapy. This work supports future translation of PDT for the treatment of spinal metastases.

Current treatment for spinal metastasis involves a multimodal approach, including bisphosphonates and radiation therapy. Yet, tumour response varies considerably, thus novel treatments or combination therapies are needed to treat these metastases while preserving stability and integrity of the spinal column. Photodynamic therapy (PDT) has been shown to be successful in destroying vertebral osteolytic tumours and enhancing vertebral structure, particularly in combination with bisphosphonates. This thesis aims to evaluate the longer-term effects of PDT alone and in combination with bisphosphonate or radiation therapy on healthy vertebrae, and the short-term effects of PDT combined with radiation therapy on healthy and metastatically-involved vertebrae. The benefits of PDT on vertebral structure, both at short-term and longer-term time-points, were greatest in combination with previous bisphosphonate therapy. Similar effects, to a lesser magnitude, were seen with PDT in combination with radiation therapy. This work supports future translation of PDT for the treatment of spinal metastases.

Lymphatic metastasis in breast cancer (BC) is one of the most important prognostic factors for patient survival. The escaped tumor cells reach distant vital organs and their unopposed expansion in these organs may cause mortality to patient. Tumor cells are transported to lymph node (LN) exclusively by tumor lymphatic vessels (LV). Increased tumor lymphangiogenesis, i.e., the formation of new LV is currently thought to be promoted by soluble factors such as VEGF-C and –D that activate VEGFR-3 expressed in lymphatic endothelial cells (LEC). These factors are secreted by malignant, tumor-infiltrating immune and stromal cells and create a favorable environment for formation of new vessels. However, emerging evidence suggests that tumor lymphangiogenesis is also promoted by Myeloid-derived Lymphatic Endothelial Cell Progenitors (M-LECP). We recently showed that M-LECP are abundant in mouse and human breast tumors and that their density strongly correlates with both lymphatic formation and nodal metastasis. Characterization of M-LECP showed that nearly all these cells express typical markers of the M2-type of macrophages such as CD163, CD204, and CD209. These cells are consider to be strongly immunosuppressive as exemplified by their inhibition of mobilization, activation, and survival of the key defenders against cancer cells, cytotoxic CD8+ T lymphocytes. Here, we compare the in vitro differentiation of M-LECP derived from bone marrow (BM) myeloid precursors primed with CSF-1 followed by secondary stimulants such as LPS, an immunomodulatory ligand for TLR4, and IL-4, IL-13, and IL-10 downstream targets of this receptor that are known to promote M2-macrophage development. Expression of these stimulants was analyzed by qPCR, flow cytometry, and ELISA during M-LECP differentiation. Our study describes the expression and functionality of these Th2 cytokines and their receptors during M-LECP differentiation. We found that each of the Th2 pathways singularly promotes M-LECP differentiation but there is an absent additive effect. We also found that IL-10 but no other Th2 cytokines is upregulated along with its receptor and contributes to the expression of the lymphatic properties similarly to LPS. To our knowledge, the role of IL-10 in development of lymphatic phenotype through differentiation of M-LECP has not been reported previously. Lastly, we show recruitment of M-LECP in a mouse BC model and the co-expression of the Th2 cytokine receptors in these cells. These studies have a potential to identify new regulators of M-LECP production in the bone marrow that could serve as biomarkers and targets for inhibiting tumor lymphatic formation, and by extension, lymph node metastasis.

No description available.