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Regulation Of Gastric Tumour Invasion And Growth By Gp130 Activating Cytokines.
Funder
National Health and Medical Research Council
Funding Amount
$625,642.00
Summary
Gastric cancer is a major cause of morbidity and death worldwide. We have previously established a very informative animal model of this disease which has facilitated a new understanding of the diverse role of the IL-6 family of cytokines in regulating gastric tumour growth and dissemination to distant organs. This proposal will focus on how the main members of this cytokine family, namely IL-6 and IL-11, inhibit gastric tumour invasion to other organs, and promote tumour growth respectively . A ....Gastric cancer is a major cause of morbidity and death worldwide. We have previously established a very informative animal model of this disease which has facilitated a new understanding of the diverse role of the IL-6 family of cytokines in regulating gastric tumour growth and dissemination to distant organs. This proposal will focus on how the main members of this cytokine family, namely IL-6 and IL-11, inhibit gastric tumour invasion to other organs, and promote tumour growth respectively . An understanding of these processes will aid in designing therapeutic interventions specific for each cytokine and which may lead to drugs aimed at limiting or reversing this disease.Read moreRead less
Inhibition Of Breast Cancer Metastasis Through Targeting Of Laminin-10 Function
Funder
National Health and Medical Research Council
Funding Amount
$391,241.00
Summary
Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have sp ....Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have spread to bone and lungs suggesting that this protein may play a role in the dissemination of breast cancer cells to other organs. Consistent with this, we have found that laminin-10 stimulates breast tumour cell adhesion and movement in culture, two activities required for successful metastasis of tumour cells. The overall objective of the projects is to demonstrate that breast cancer metastasis can be inhibited by interefering with the function of laminin-10. To this end, we will measure the effect of blocking the production of LN-10 in breast tumour cells on their ability to metastasise. Alternatively, we will test fragments of laminin-10 for their ability to block laminin-10-induced tumour cell growth and movement (required for their escape from the breast) and viability (required for their establishment in distant organs). We will generate antibodies against the most inhibitory fragments and test their effect on spontaneous metastasis in a clinically relevant mouse model of breast cancer metastasis in an attempt to stop-reverse the progression of the disease. If successful, this project will provide the foundation for the development novel inhibitors targeting laminin-10 for the treatment of patients with advanced breast cancer.Read moreRead less
The Function Of Histidine-rich Glycoprotein In Inflammation And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$455,670.00
Summary
This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been im ....This research proposal investiagtes the role of a molecule known as histidine-rich glycoprotein (HRG) in the important diseases of cancer and inflammation. Inflammatory diseases can occur when the the normal checks on the immune system breakdown resulting in attacks on the body leading to tissue damage (e.g rheumatoid arthritis) and are significant contributors to morbidity and health costs in Australia. Cancer is the leading cause of death in Australia (28.4% of deaths in 2003). HRG has been implicated in controlling important aspects of inflammatory and cancer disease progression. Namely, HRG appears to regulate the formation and clearance of substances known as immune complexes - the primary cause of tissue damage in this disease. Furthermore, HRG may also control the process of cell invasion which is crucial for the migration of white blood cells of the immune system (leukocytes) to sites of inflammation to combat infections, and is also an important mechanism by which malignant tumour cells escape from primary tumour sites and spread throughout the circulation to other sites in the body. It is this process that makes cancer such a deadly disease. This study aims to define how HRG contributes to these important processes. This information may allow the development of new therapeutic approaches for the treatment of inflammatory diseases and cancer.Read moreRead less
The Role Of Eph/ephrin Clustering And Trafficking In Control Of Tumour Cell Invasion
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
Eph and ephrin proteins are important for normal development of the embryo by controlling cell positioning. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where their presence is thought to promote aggressive tumours. We wish to understand how these proteins control cell movement and contribute to cancer progression so that we can develop new cancer therapies.
A Fluorescent Zebrafish Model Of Endodermal Cell Migration.
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
The most catastrophic event in cancer progression is when individual cancer cells move to other areas of the body and develop into secondary tumours. This very complex process shows striking similarities to cell movements during embryogenesis. In this project, we use a model system, the zebrafish, to analyse how cells move during embryogenesis. We will determine the genes required for cell movements in the zebrafish embryo, so we can find the corresponding genes in human cancers.
Characterisation Of The Role & Biomarker Potential Of The Novel Cell Surface Protein TTYH2 In Renal Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at ....Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at the expression of TTYH2 in more clinical samples to determine if TTYH2 will be a useful bio-marker for this cancer. We are also studying the function of this protein in renal cell carcinoma cells to identify the exact role that TTYH2 performs in cancer development and progression. Finally we will look at what other proteins are interacting with TTYH2 in kidney cancer cells. These latter studies will help us to understand the disease process better and may help us design new treatment methods.Read moreRead less
EphA3-modulated Cell Positioning In Tumour Invasion And Neovascularisation.
Funder
National Health and Medical Research Council
Funding Amount
$647,232.00
Summary
During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with co ....During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with collaborators at the Ludwig Institute for Cancer Research and the Queensland Institute for Medical Research we produced two proteins, an antibody and a recombinant ephrin that bind one of the Eph proteins on tumour cells. The antibody allowed us to locate Eph in tumours, where it appears surprisingly not only on tumour cells but also on tumour blood vessels. When attached to a redioactive compund it selectively targets the cancer cells and in an animal study prolonged the survival of mice with leukemia significantly. We will now investigate the exact role of this Eph protein in tumour blood vessels. We will then study what happens in tumours when a toxic antibody-drug compound targets this tumour and starts to kill tumour cells. Finally, we will devise a novel reagent that combines the properties of the antibody with the properties of the ephrin into a single protein, which can deliver a cell-killing drug exclusively and most efficiently to tumour cells containing the Eph protein on its surface.Read moreRead less
Development And Evaluation Of Biological Reagents Targeting And Inhibiting Function Of The EphA3 Receptor On Tumor Cells
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukem ....Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukemia and malignant melanoma. High levels of EphA3 and corresponding ligands correlate with melanoma progression, and EphA3 stimulation triggers repulsion and detachment of melanoma cells. It is likely that Eph A3 is involved in release and spreading of tumour cells during melanoma progression. We have characterised reagents, the soluble EphA3 ligand and a monoclonal anti-EphA3 antibody, which bind EphA3 with high affinity and specificity. We will use these two proteins, or modified forms containing attached radiochemicals or cytotoxins, to target human tumours that were implanted into into immuno-deficient mice as animal model system. Our studies will determine if the specificity of our reagents, suggested from previous in-vitro studies, will allow imaging of EphA3 containing tumours, and effect their targeted killing. We will also use a tissue culture model, containing artificial epidermal and dermal layers of skin cells, to study if an inhibitory form of the EphA3 ligand will affect the invasiveness of EphA3 positive, metastatic melanoma cells. Furthermore, we will identify essential parts of this ligand to develop inhibitors with improved pharmacological properties. Together, our studies will establish the role for EphA3 in cancer progression and to assess the efficacy of EphA3 targeting for tumor killing and prevention of metastasis. We envision that this will provide the groundwork for Eph-specific reagents with anti-metastatic action in cancer therapy.Read moreRead less
Differential Cooperation Of MAPKs With TGF-beta Signaling In Epithelial-Mesenchymal Transition
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identi ....Tumor metastasis - the spread of tumor cells from the original site of growth to other sites in the body, is the biggest threat to survival for patients with solid tumors. The most damage change during cancer progression is the switch from a locally growing tumor to a metastastic killer. For biologist studying cancer, a major challenge is to identify the molecular and cellular mechanisms underlying the switch of non-invasive tumor to an invasive, metastatic state. This application aims to identify key molecular and cellular mechanism controlling this switch, with the ultimate aim being to devise treatments that inhibit tumor metastasis. The results from this work will provide clear and specific targets to prevent and to treat tumor metastasis. More importantly, the success of strategies used in this work can potentially be used clinically for tumor treatment.Read moreRead less