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 objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAG ....The objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAGs act as growth factors for the normal gastric and colonic mucosa, accelerate the development of both gastric and colorectal cancer, and may be involved in iron overload. The specific aims are: (1) to determine whether or not ferric ions are essential for the stimulation of colorectal carcinoma (CRC) development by NAGs in vivo, (2) to develop orally active NAG inhibitors and analogues, and (3) to confirm the relationship between NAGs and iron status in mice and extend these observations to humans. The research design mirrors the specific aims, and utilises the unique combination of skills of the chief and associate investigators. Firstly, agents (desferrioxamine and bismuth ions) known to block the binding of ferric ions to NAGs will be tested as NAG inhibitors in 4 animal models of CRC development. Secondly, orally active relatives of desferrioxamine and structurally modified gastrin fragments will be tested in CRC cells and in animal CRC models as NAG inhibitors and analogues, respectively. Thirdly, serum gastrins will be measured in mice with altered dietary iron uptake, and in patients with iron overload. These studies are expected to confirm the reciprocal relationship between gastrin concentrations and ferric ion homeostasis observed in mice, and to demonstrate that a similar connection exists in humans. Recognition that metal ions are essential for the biological activity of NAGs may permit the development of novel therapies for colon cancer and iron overload.Read moreRead less
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
Peptides Derived From ProGRP As Growth Factors For Gastrointestinal Cancers
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Our objective is to determine the roles of a growth factor termed bombesin. This peptide, known as GRP in the human, is a growth factor in certain lung cancers but little is known about its role in tumours of the colon. This project is based on our novel observation that the precursor of GRP (proGRP) previously thought to be inactive is in fact active in stimulating the growth of colon cancer cells. A successful outcome will result in novel treatments such as proGRP antagonists.
Identification Of The Gene For A Novel Syndrome Of Gastric Adenocarcinoma And Proximal Polyposis Of The Stomach (GAPPS)
Funder
National Health and Medical Research Council
Funding Amount
$378,152.00
Summary
We have identified a previous undescribed syndrome of multiple polyps in the stomach, and a tendency to develop stomach cancer. We are now want to identify the gene responsible, and to determine if it plays a part in the development of other cancers that occur outside people with this rare syndrome.
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 their 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 deterrmine the potential roles of a growth factor termed bombesin. This peptide, now known as GRP ....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 their 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 deterrmine the potential roles of a growth factor termed bombesin. 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. This project is based on our novel observation that the precursor of GRP (proGRP) previously thought to be inactive is in fact biologically active in stimulating the growth of colorectal carcinoma cells. We will determine which parts of the GRP precursor (proGRP) are bioactive, and test the effects of the bioactive regions on growth and cancer spread using a variety of colorectal cancer cell lines. We will also investigate the effects of the bioactive regions of proGRP on the development of colorectal cancer in three animal models, which represent different stages of the progression to invasive cancer. We will then compare the intracellular pathways by which proGRP and GRP communicate with the cell nucleus, and investigate the structure of the cell-surface receptor that binds the proGRP. Finally we will determine the types and amounts of proGRP derived peptides produced by CRC cell lines and by tumours obtained from patients with colorectal cancer. 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 proGRP receptor antagonists and radioactive proGRP analogues for radiotherapy.Read moreRead less
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.