Gene Expression And DNA Methylation In Barrett's Oesophagus And Oesophageal Adenocarcinoma
Funder
National Health and Medical Research Council
Funding Amount
$383,655.00
Summary
The oesophagus (gullet) is the tube through which food and drinks pass from the mouth to the stomach. In Barrett's oesophagus, the normal lining of the lower oesophagus is replaced by an abnormal type of lining called intestinal metaplasia as a result of severe gastroesophageal reflux. Gastroesophageal reflux is one of the most common of all diseases, affecting up to a quarter of all adults, and Barrett's oesophagus itself occurs in 0.5 - 1% of the adult population. In a minority of patients wit ....The oesophagus (gullet) is the tube through which food and drinks pass from the mouth to the stomach. In Barrett's oesophagus, the normal lining of the lower oesophagus is replaced by an abnormal type of lining called intestinal metaplasia as a result of severe gastroesophageal reflux. Gastroesophageal reflux is one of the most common of all diseases, affecting up to a quarter of all adults, and Barrett's oesophagus itself occurs in 0.5 - 1% of the adult population. In a minority of patients with Barrett's oesophagus, further abnormalities in the cells lining the lower oesophagus occur, leading to dysplasia and adenocarcinoma (glandular cell type cancer). This project will provide the first comprehensive map of two of the most important genetic mechanisms (gene expression and DNA methylation) by which Barrett's oesophagus evolves into Barrett's dysplasia and adenocarcinoma. The specimens studied in this project differ from previous studies in that they are taken from the same patients at different times, as these patients' Barrett's oesophagus either remains stable or progresses to worse disease. Essentially all the known human genes will be studied and the relevance of genes identified as important will be confirmed using highly accurate methods. With this information, it may be possible to develop genetic tests that can predict which patients are at risk of developing worse disease including cancer. In other parts of this project, genes which influence the likelihood of survival for patients with oesophageal adenocarcinoma will be identified, a simple test to more accurately identify patients with cancer spread to lymph nodes may be developed, and a blood test to detect oesophageal adenocarcinoma will be tested.Read moreRead less
Reevaluation Of The Anatomy Of The Human Lymphatic Vessel Network
Funder
National Health and Medical Research Council
Funding Amount
$539,750.00
Summary
The mode of spread of cancer cells from a primary tumour to other parts of the body is still not completely understood, although the lymphatic system is known to be important in this process. Lymph vessels are tiny transparent channels that form a network over the entire body. They transport tissue fluid to regional lymph glands in the neck, armpits, groin, chest and abdomen where the immune response maybe initiated to combat foreign agents such as bacteria and cancer cells. Current knowledge of ....The mode of spread of cancer cells from a primary tumour to other parts of the body is still not completely understood, although the lymphatic system is known to be important in this process. Lymph vessels are tiny transparent channels that form a network over the entire body. They transport tissue fluid to regional lymph glands in the neck, armpits, groin, chest and abdomen where the immune response maybe initiated to combat foreign agents such as bacteria and cancer cells. Current knowledge of the anatomy of these tiny vessels is based on work done by Sappey more than a century ago. There is an urgent need to update this work as many of his conclusions have been found to be inaccurate. We will use our pioneering methods of microsurgical tissue transfer- now being used worldwide - and our extensive experience in delineating fine channels, to address some of the basic questions about the anatomical pathways of spread of cancer. We hope to discover for example: why cancer on one side of the back can spread to glands in the opposite groin or armpit, thought by Sappey to be impossible; why cancer on one side of the tongue can spread to lymph glands on the opposite side of the neck; and why there is sometimes swelling of the limbs following lymph gland ablation by surgery or radiotherapy of glands in the groin or armpit. Currently it is thought that the only major connections with the venous system are at the base of the neck. Our initial work has shown unexpected connections with blood vessels in the periphery and unreported lymphatic vessel pathways between the skin and deep tissues. The results of this research will give information that will aid in localizing and treating the spread of malignancies and will underlie future treatment of obstructed lymph vessels that are the cause of painful, disabling swelling (lymphoedema) of the limbs.Read moreRead less
Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western soc ....Until recently, cancer of the oesophagus was a very uncommon tumour in Australia and other western populations. However during the past three decades, there have been very large increases in the incidence of this disease. Indeed, rates of oesophageal cancer have risen faster than any other cancer in the United Statesand similar dramatic increases in incidence have been observed in Europe and Australia. With increasing population prevalence of the causes of cancer of the oesophagus in western societies (namely acid reflux, obesity and poor diet), there are strong grounds for predicting that incidence will continue to rise, and that oesophageal cancer will constitute an increasingly large burden on society. Unfortunately, treatment options are limited, survival is often short, and there is no way of identifying which tumours will respond to therapy. This proposal will collect treatment and health outcomes data for a population-based cohort of patients with oesophageal cancer. The goal is to identify prognostic and predictive markers to aid patients and clinicians when making treatment decisions, as now exist for breast cancer. Such markers may also serve as novel targets for therapy. The proposed study builds upon the platform of the Australian Cancer Study [ACS], one of the world's largest studies of oesophageal cancer. This represents a unique opportunity to investigate a pressing clinical problem by building upon a study of acknowledged international importance.Read moreRead less
Australasian Randomised Clinical Trial Comparing Laparoscopic And Open Surgical Treatment Of Colon Cancer: Follow-up.
Funder
National Health and Medical Research Council
Funding Amount
$233,000.00
Summary
Colon cancer is one of the most common solid tumours in western society. The usual initial treatment is excision of the cancer by an operation done through a cut down the midline of the abdominal wall. Over the past 15 years, minimally invasive technology has changed the approach to many surgical operations. A good example of this is an operation to remove the gall bladder. This is now routinely done using a laparoscope (telescope) which is introduced at the umbilicus. An image on a video screen ....Colon cancer is one of the most common solid tumours in western society. The usual initial treatment is excision of the cancer by an operation done through a cut down the midline of the abdominal wall. Over the past 15 years, minimally invasive technology has changed the approach to many surgical operations. A good example of this is an operation to remove the gall bladder. This is now routinely done using a laparoscope (telescope) which is introduced at the umbilicus. An image on a video screen of the gall bladder is then used to guide instruments to remove the gall bladder without making a large incision in the abdominal wall. This is called a laparoscopic cholecystectomy. The safety of a laparoscopic assisted approach in the removal of colon cancer is yet to be determined. This study will compare the long term and short term outcomes of people who have colon cancers removed whether by laparotomy ( a cut in the midline of the abdominal wall) or by a laparoscopic assisted approach (telescope).Read moreRead less
Ablative Therapies For Barrett's Oesophagus - Evaluation Of New Clinical And Experimental Therapies
Funder
National Health and Medical Research Council
Funding Amount
$302,310.00
Summary
Barrett's oesophagus arises when repeated episodes of gastro-oesophageal reflux lead to the oesophageal lining undergoing change to a lining more like that of the intestine. This new lining predisposes to cancer, a problem which is rapidly becoming more common. Recent research has focused on techniques which could reverse this process. Destruction (ablation) of Barrett s oesophagus can be followed by regeneration with a normal looking lining. A range of techniques have been used for this. Howeve ....Barrett's oesophagus arises when repeated episodes of gastro-oesophageal reflux lead to the oesophageal lining undergoing change to a lining more like that of the intestine. This new lining predisposes to cancer, a problem which is rapidly becoming more common. Recent research has focused on techniques which could reverse this process. Destruction (ablation) of Barrett s oesophagus can be followed by regeneration with a normal looking lining. A range of techniques have been used for this. However, the behavior of the regenerated lining is unknown, and there still remains potential for cancer. We are currently evaluating endoscopic ablation using Argon Plasma Coagulation within clinical trials. There is also scope for the development of better approaches to ablation. We hypothesize that an suitable liquid has the potential to more evenly and more easily ablate the lining. Delivery of a liquid substance to lower oesophagus can be achieved through a tube which confines liquid to the lower oesophagus. However, to make this approach acceptable it is necessary to determine the best treatment agent, and to test the delivery system. We will first do this using animal models, before future application in patients. A further key issue is whether the cells which repopulate the oesophagus are genetically normal or abnormal. After ablation it is likely that the cells which repopulate the lining are sourced from the same cells which were the source of the abnormal lining, and these cells could inherit genetic alterations. This could increase the risk of cancer. Hence, we plan to assess certain genes in biopsies taken from tissue before and after ablation to determine genetic normality. In Australia endoscopic ablative techniques are currently being introduced into clinical practice without evaluation. Hence the question of whether ablation actually reduces the risk of cancer and how to best perform ablation should be addressed before clinical application becomes widespread.Read moreRead less
Alternative Insufflation Gases For Laparoscopic Surgery
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
It is now recognised that laparoscopic (keyhole) surgery for cancer can be associated with the spread of tumour to surgical wounds, i.e. port sites. However, whether this is more likely following laparoscopy than conventional open surgery is controversial. Isolated case reports and the recent results of experimental studies suggest that the problem is important. Previous studies suggest that carbon dioxide gas used to inflate the abdomen during laparoscopy may be the specific cause of this probl ....It is now recognised that laparoscopic (keyhole) surgery for cancer can be associated with the spread of tumour to surgical wounds, i.e. port sites. However, whether this is more likely following laparoscopy than conventional open surgery is controversial. Isolated case reports and the recent results of experimental studies suggest that the problem is important. Previous studies suggest that carbon dioxide gas used to inflate the abdomen during laparoscopy may be the specific cause of this problem. A four to fivefold increase in the rate of cancer spread has been shown in previous experiments, and this can be reduced by using an inert gas such as helium. We propose to further investigate this issue using a combination of small and large animal models, and will also commence clinical trials of helium during clinical surgery. These studies aim will determine the gas of choice during laparoscopic surgery. They will also clarify advantages demonstrated for the use of helium in previous animal studies, and better investigate the safety of helium use. If our preliminary findings are supported by these studies, helium (or other inert gases) should be considered for routine use during clinical laparoscopy.Read moreRead less
AUSTRALASIAN MULTICENTRED PROSPECTIVE RANDOMISED STUDY OF LAPAROSCOPIC VS CONVENTIONAL SURGICAL TREATMENT OF COLON CA
Funder
National Health and Medical Research Council
Funding Amount
$495,000.00
Summary
Colon cancer is one of the most common solid tumours in western society. The usual initial treatment is excision of the cancer by an operation done through a cut down the midline of the abdominal wall. Over the past 10 years, minimally invasive technology has changed the approach to many surgical operations. A good example of this is an operation to remove the gall bladder. This is now routinely done using a laparoscope (telescope) which is introduced at the umbilicus. An image on a video screen ....Colon cancer is one of the most common solid tumours in western society. The usual initial treatment is excision of the cancer by an operation done through a cut down the midline of the abdominal wall. Over the past 10 years, minimally invasive technology has changed the approach to many surgical operations. A good example of this is an operation to remove the gall bladder. This is now routinely done using a laparoscope (telescope) which is introduced at the umbilicus. An image on a video screen of the gall bladder is then used to guide instruments to remove the gall bladder without making a large incision in the abdominal wall. This is called a laparoscopic cholecystectomy. The safety of a laparoscopic assisted approach in the removal of colon cancer is yet to be determined. This study will compare the long term and short term outcomes of people who have colon cancers removed either by a laparotomy (a cut in the midline of the abdominal wall) or by a laparoscopic assisted approach (telescope).Read moreRead less
Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less