Our objective is to understand the biological significance of the interaction between iron and the hormone gastrin. The project's significance to human health lies in the fact that gastrins stimulate growth of the lining of the stomach and colon, accelerate the development of gastrointestinal cancers, and may be involved in iron homeostasis. Recognition that iron is essential for the biological activity of gastrins may allow the development of novel therapies for colon cancer and iron overload.
The Mechanism Of Action Of Progastrins In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$378,000.00
Summary
Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind ga ....Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind gastrin precursors to the surface of colon cells, and to understand how receptor binding triggers changes in the colon which result in CRC development. Our recent discovery that gastrin precursors promote cell migration by reducing adhesion between cells is particularly significant from the perspective of CRC because of the potential importance of this phenomenon in the early stages of cancer development. Our recent observation that gastrin precursors bind metal ions with high affinity further suggests that metal binding may be essential for receptor binding and hence for biological activity. We will therefore investigate: (1) whether binding of metal ions to gastrin precursors effects biological activity, (2) which regions of gastrin precursors are required for receptor binding, (3) the structures of the receptors which bind gastrin precursors to colon cells, (4) the pathways which connect the receptors to other intracellular proteins that maintain contact between adjacent cells, and (5) the differences between the pathways controlling adhesion and the pathways controlling cell growth. This project should lead to a detailed understanding of the molecular mechanisms underlying the effect of gastrin precursors on colon cell growth and adhesion. Definition of the receptors and intracellular signalling mechanisms involved may ultimately lead to novel treatments for disorders of colonic proliferation including CRC.Read moreRead less
Elucidation Of Mechanisms By Which Fibre Promotes Or Protects From Colorectal Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer develop ....In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer development have factors in their faeces that affect the health of the cells that line the colon (the ones that form the cancers). This will be examined in both the test tube and in healthy rats. Whether fibres influence the access of these factors to the lining cells by sequestering or hiding the factors in the jelly-like consistency some fibres produce in the colon will also be examined. The results will help identify conditions in the faeces that alter the susceptibility of colons to developing cancer. By identifying these conditions, we can then apply our knowledge to human subjects, so that we might be able to identify those at a higher or lower risk of developing colon cancer and we can advise and (subsequently prove) ways of modifying diet to reduce the risk of colon cancer.Read moreRead less
Functions Of FZD7 In The Intestine And Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$644,761.00
Summary
Wnt proteins are a family of signaling molecules that are critical for the function of normal and cancerous epithelial cells in the gut. However, the cell surface receptor that transmits Wnt signals is not known. Our research strongly implicates one Wnt receptor (FZD7). Here we test this using innovative mouse and cell line models. We wish to understand how Wnt-driven processes are activated. This knowledge will lead to novel avenues to block aberrant activation of Wnt signalling in cancer cells
Physiology And Pathology Of Novel Forms Of Progastrin
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Gastrin is a stomach hormone which increases acid secretion and the growth of the stomach and bowel. This growth promoting effect may be involved in a number of cancers especially colon cancer. The different types of gastrins have different effects but we do not know which forms are important and whether all are active. The types and activity of the different gastrins will be investigated using cell lines, animal models and colon cancer patients with the view of establishing new treatments.
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.
Bombesin Like Peptides As Autocrine Growth Factors In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$406,980.00
Summary
Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce its own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to determine the potential roles of a growth factor termed Bombesin Like Peptide. This peptide, now kn ....Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. Colorectal carcinomas in common with other cancer types such as cancer of the prostate and lung often produce its own growth factors and receptors. Activation of the receptor by the growth factor further stimulates the tumour's growth and spread throughout the body. The objective of this project is to determine the potential roles of a growth factor termed Bombesin Like Peptide. This peptide, now known as GRP in mammalian systems, is an established growth factor in certain lung cancers but little is known about its role in tumours of the large bowel. We will study the expression and production of GRP and its receptors at the gene and protein level, the ability of GRP to stimulate growth, the chemical structures of GRP, and the potential of antagonists of GRP to modulate growth. Studies will be performed in patients with bowel cancer, in animal models of bowel cancer, and with bowel tumours removed from patients and bowel cancer cell lines. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as GRP receptor antagonists and radiolabelled GRP analogues for radiotherapy.Read moreRead less
The Role Of Differentially Methylated Genes In The Initiation And Progression Of Colorectal Cancers
Funder
National Health and Medical Research Council
Funding Amount
$361,527.00
Summary
Most colorectal cancers develop from polyps in the lining of the bowel. The bulk of cancers develop from adenomatous polyps, but we have found that a second type of polyp called a hyperplatic polyp can also be associated with the development of cancer. During our studies of these polyps we found that a particular gene was inactivated in all of these polyps. We have called this gene HPP1. HPP1 was also found to be inactivated in adenomatous polyps and about 50% of colorectal cancers, indicating t ....Most colorectal cancers develop from polyps in the lining of the bowel. The bulk of cancers develop from adenomatous polyps, but we have found that a second type of polyp called a hyperplatic polyp can also be associated with the development of cancer. During our studies of these polyps we found that a particular gene was inactivated in all of these polyps. We have called this gene HPP1. HPP1 was also found to be inactivated in adenomatous polyps and about 50% of colorectal cancers, indicating that it may be an important player in the early stages of colorectal cancer and hence may allow opportunity for prevetive intervention. This grant proposal will investigate the function of HPP1 in the genesis of colorectal polyps and cancers.Read moreRead less
Characterisation Of Precursor Lesions In Colorectal Cancers With DNA Instability
Funder
National Health and Medical Research Council
Funding Amount
$60,190.00
Summary
It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely differ ....It is now generally accepted that most colorectal cancers arise from previously benign lesions in the mucosal lining of the large bowel. These lesions are called adenomatous polyps. They have been extensively studied as have the cancers which evolve from them with regard to the type of cancer causing genetic changes they bear. Recently, it has been found that colorectal cancer is not a single disease in that there exists a subgroup comprising 15% of colorectal cancers which is an entirely different type wwith respect to genetic changes and biological behaviour. This subgroup contains cancers with a high level of microsatellite instability (MSI-high) and the cancers which comprise this group show none of the common genetic changes which can be demonstrated in both adenomatous polyps and the 85% of colon cancers which develop from them. The MSI-high colorectal cancers do however share some striking similarities to a type of polyp (hyperplastic) which has until quite recently been considered of little consequence. Our research group and others have shown an association with colorectal cancer in those patients in whom hyperplastic polyps are unusually large or numerous, especially if present in the right side of the large bowel, where the bulk of MSI-high colorectal cancers arise. The current proposal will investigate the hyperplastic polyp as a precursor lesion in the genesis of MSI-high cancers.Read moreRead less