Microparticles As Novel Biomarkers In Liver Cancer
Funder
National Health and Medical Research Council
Funding Amount
$85,833.00
Summary
No current highly sensitive or specific diagnostic and prognostic biomarker for hepatocellular carcinoma (HCC) exists. We will identify novel nucleic acid signatures in the circulation of patients with HCC through Next Generation Sequencing. Plasma microvesicles will be isolated and their contents analyzed to identify novel genetic biomarkers and fusion gene constructs specific for HCC. Resultant panel of novel biomarkers for HCC will be validated on the Australian STREP cohort of HCC patients.
The Role Of Adiponectin In Hepatocellular Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$125,922.00
Summary
Primary liver cancer or hepatocellular carcinoma is a leading cause of cancer deaths worldwide and accounts for approximately 1000 deaths in Australia annually with a rising incidence in both men and women. It is associated with chronic viral hepatitis and liver cirrhosis. Even in patients with viral hepatitis, obesity has been shown to increase the risk of cirrhosis and liver cancer. This study will investigate the role of the fat tissue derived molecule adiponectin in liver cancer.
THE ROLE OF THE HEPATOCYTE HEDGEHOG PATHWAY IN PROGRESSIVE LIVER INJURY
Funder
National Health and Medical Research Council
Funding Amount
$570,876.00
Summary
This research plan investigates the role of a pathway, known as the Hedgehog pathway, in the development of liver disease which can result in end-stage scarring known as cirrhosis and even lead to liver cancer (known as Hepatocellular carcinoma). Hepatocellular carcinoma is the globally the third most common cause of cancer death and our research will help to better understand how liver injury develops and how this then leads to liver cancer.
I am a Gastroenterologist who has established major research programs in the broad areas of the pathogenesis of Hereditary Haemochromatosis, the role of hepatic stem cells in the pathogenesis of liver cancer and colorectal cancer screening.
The Role Of TNF And Its Receptor Family In Liver Progenitor Cell Proliferation And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$250,500.00
Summary
Maintaining liver function is essential for health, and compromising this ultimately results in death. The liver is unusual, as it can regenerate to replace lost or damaged tissue. Recently it has been established that there are two pathways to liver regeneration. One involves hepatocytes, and this is normally associated with acute liver damage. The other, involves liver progenitor cells; and this is usually observed when there is chronic and severe liver damage, particularly when the proliferat ....Maintaining liver function is essential for health, and compromising this ultimately results in death. The liver is unusual, as it can regenerate to replace lost or damaged tissue. Recently it has been established that there are two pathways to liver regeneration. One involves hepatocytes, and this is normally associated with acute liver damage. The other, involves liver progenitor cells; and this is usually observed when there is chronic and severe liver damage, particularly when the proliferation of hepatocytes is impaired. This study seeks to understand the underlying mechanisms which recruit liver progenitor cells for regeneration. This knowledge can lead to strategies to augment the oval cell contribution to liver regeneration in cases of chronic liver damage, to enhance survival of the patient. It can be applied to strategies to grow and maintain liver stem cells in culture for the purpose of cell and gene therapy to correct liver dysfunction. It is also necessary to identify factors which affect oval cells and understand their mechanism of action because of their link to liver cancer. Oval cells have a Jekyll and Hyde characteristic, and it is important to know what leads them towards liver differentiation and regeneration, and what makes them produce liver cancers.Read moreRead less
TGF-beta Receptor Type III In Normal And Malignant Liver Growth: Modulation Of TGF-beta Activity
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, ter ....The transforming growth factor-beta (TGF-beta) family is a group of multifunctional growth factors which regulates a number of important cellular functions, including proliferation, differentiation, and survival. Therefore, the proper functioning of this system is critical for the normal development and maintenance of most tissues. Dysregulation of this system is implicated in many pathological conditions, including cancer. The actions of TGF-beta are mediated by three cell surface proteins, termed the type I, II and III TGF-beta receptors. The type I and II receptors are required for transmitting the TGF-beta signal to the nucleus of the cell. Existing data suggest that the type III receptor is not required in TGF-beta signaling but is required for the regulation of TGF-beta levels at the cell surface. However, the function of this receptor and its role in TGF-beta mediated regulation of cell growth and survival is poorly understood. Our earlier work indicated that the TGF-beta type III receptor is particularly important for limiting TGF-beta activity during normal liver development. The currently proposed research will examine the effects of type III receptor deficiency on liver cells in the adult mouse in order to determine whether alterations in cell growth and survival occur in the absence of this receptor. Becauses TGF-beta is a key regulator of liver growth and altered levels of TGF-beta in liver have been demonstrated to lead to liver cancer in mice, we anticipate that targeting the deletion of the type III gene to liver cells will provide a system in which to study compromised regulation of cell growth. This work is therefore expected to yield information relevant to the role of this receptor in TGF-beta regulated processes in normal and cancerous growth. Because the type III receptor appears to control the level of TGF-beta activity, this work will allow further evaluation of the potential for therapeutic uses for type III receptor-like agents.Read moreRead less
Apo2L/TRAIL Killing Of Tumour Cells And The Role Of Inhibitor Of Apoptosis Proteins
Funder
National Health and Medical Research Council
Funding Amount
$390,321.00
Summary
Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Al ....Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Although we will not personally test these drugs in clinical settings, these drugs or similar are currently in preclinical and clinical trials. This means that understanding how these drugs function is of paramount importance and may result in better clinical trials and possibly more rapid acceptance of the use of these drugs in patients.Read moreRead less
DNA Repair Mechanisms In The Pathogenesis Of Hepatocellular Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$339,078.00
Summary
Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of in ....Hepatocellular carcinoma (HCC) or cancer originating in the liver ranks 5th in worldwide frequency among tumours, and is the 3rd highest cause of cancer in our region. The incidence is increasing in most countries including Australia, Japan and USA. The overall prognosis is poor, with >80% affected persons dying from this disorder. The risk factors for HCC are well known and include chronic hepatitis B or C virus infection, alcoholism and liver iron accumulation. Despite the vast amount of information available regarding these risk factors, the way in which they alter normal liver cells to make them cancerous remains undefined. The majority of liver cancers, regardless of cause, develop in severely scarred, or cirrhotic liver in the presence of chronic liver inflammation. Such an environment causes liver cells, which are usually stable and not dividing, to continue replicating in response to injury; such continued cell division can lead to damaged genetic information in the DNA of these cells. Many cancers are associated with chromosomal damage, including broken ends and deleted genetic material. The main focus of this project to investigate how defective repair of disrupted genetic information contained in DNA of chromosomes in damaged liver cells contributes to the development of liver cancer. Using mice lacking specific genetic information to repair DNA double strand breaks, we plan to investigate whether abnormalities in DNA repair mechanisms in liver cells damaged by diethylnitrosamine (DEN) predisposes liver cells to regenerate abnormally thereby progressing to cancer. We have clues that 7 specific sites in chromosomes where loss of key genes may promote HCC formation. These studies will greatly enhance our understanding of the molecular basis by which HCC develops. The ultimate goal of this research is to develop effective screening and treatment strategies to prevent or interrupt the process of liver cancer development in at-risk individuals.Read moreRead less