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Current Research Projects

Oesophageal and Colorectal Cancer

Obesity has increased markedly over the past two decades and while numerous epidemiological studies have established a significant association between obesity and cancer, with obesity estimated to account for up to 20% of cancer deaths, the underlying mechanisms remain unclear. A state of low-grade chronic inflammation exists in obese individuals and this is thought to be a major contributing factor for the increased incidence of a range of cancers, including oesophageal and colorectal adenocarcinoma. Visceral adiposity, in particular, is a major risk factor for the development of inflammation, the metabolic syndrome and cancer. The majority of studies to date on obesity-associated inflammation have examined adipose tissue macrophages and their role in exacerbating this inflammation. However, more recent animal studies have pointed to T cells as key regulators in the initiation and maintenance of obesity-associated inflammation. However, the activation status and role of T cells in human visceral adipose tissue inflammation has not been examined to date.

The aim of this research project is to study adipose tissue from patients undergoing resective surgery for oesophageal and colorectal cancer, to investigate the mechanisms where obesity may contribute to the development and progression of these malignancies. Visceral abdominal fat has been identified as the essential fat depot for patho-genetic theories that relate obesity, metabolic syndrome and cancer. In a prospective study, subpopulations of immune cells, including T cells, in freshly digested, resected subcutaneous and omental adipose tissue are being characterised and analysed in order to determine how obesity status and cancer can affect innate and adaptive immune cells. Innate and adaptive immune cells are also being assessed in matched peripheral blood to determine how excess adipose tissue may regulate systemic immune responses, potentially affecting the anti-tumour immune response.

In a retrospective study, the activation status and localisation of distinct immune cells within the tumour microenvironment is being determined by immunohistochemistry using specifically generated tissue micro-arrays. IHC data is then be correlated with clinical parameters including BMI, visceral adiposity, metabolic syndrome status, pathological features and overall survival in order to examine the anti-tumour immune response in obese patients.

On completion of this project, which is currently funded by a HRB Fellowship award, it is anticipated that our knowledge of the regulatory mechanisms linking obesity, metabolic syndrome, immunomodulation and tumour growth will be greatly enhanced. It is hoped that potential immuno-therapeutic targets will be identified which could prevent or slow the progression of a number of obesity-associated pathologies including cancer.

Molecular interactions in obesity and cancer

The prevalence of obesity has increased markedly over the past two decades contributing to morbidity and mortality worldwide in the form of increasing rates of cardiovascular disease, diabetes and many types of cancer.  Mirroring the massive increase in obesity, the incidence of oesophageal adenocarcinoma in Ireland has doubled over the last 15 years and obesity has been identified as an independent risk factor for development of this cancer.

In addition, obesity has been linked to increased mortality following cancer development and therefore could contribute not only to increased cancer incidence but also to increased tumour progression.  A detailed investigation of the molecular mechanisms linking obesity and cancer is required. A recent study showed that abdominal obesity rather than body mass index (BMI) or general overweight is associated with oesophageal adenocarcinoma.  This suggests that the metabolic activity of abdominal fat (different to subcutaneous fat found directly underneath the skin) may play a role.

Oesophageal cancer is an aggressive disease associated with a poor five year survival of only 15 % (National Cancer Registry Ireland, 2000-2005) due in part to early lymphatic and haematogenous spread implying that pathways involved in tumour invasion and metastasis are of great significance.  The aim of this research project is to examine the molecular interactions between fat cells (adipocytes) and tumour cells in the context of oesophageal adenocarcinoma.  We want to establish if fat can fuel pathways to make a tumour more aggressive.

Our research group has established a fat biobank from patients undergoing surgery for oesophageal adenocarcinoma.  Following the patient’s consent two fat samples are collected during surgery, one from the abdominal cavity and one from directly underneath the skin (subcutaneous).  In the lab, differences in the fat from obese and non obese patients and from abdominal and subcutaneous sites are examined.  Fat tissue secretes metabolically active molecules called adipokines which could enhance the ability of the tumour to survive and grow in the body.  To investigate this, tumour cell lines grown in the lab are exposed to fat cells and/or fat derived molecules to determine their effect on tumour cells.  Some of our preliminary findings show that fat can increase tumour growth and movement, causing tumour cells to become more aggressive.  The next step is to determine the mechanisms by which fat can alter tumour cells in this way.

By furthering our knowledge of these critical biological mechanisms linking obesity and cancer we can pave the way for the development of novel therapeutic strategies and interventions to prevent and treat this disease.

An investigation into the impact of nutritional status on immune response and recovery in patients undergoing resective surgery for gastrointestinal surgery

Obesity is associated with the pathogenesis of several cancer types, including oesophageal and colorectal cancer. The increased cancer incidence in obese individuals is believed to be associated with the presence of excess visceral, or centrally located, fat. Visceral adipose tissue is metabolically active and secretes a number of biological compounds that alter the function of the immune system and can influence tumour initiation and progression. Visceral obesity also gives rise to a state of abnormal lipid metabolism, insulin resistance and inflammation, collectively referred to as the metabolic syndrome.

Patients receiving curative treatment of gastrointestinal cancer undergo major resective surgery and may have additional chemoradiotherapy. This treatment places a great metabolic stress on the patient and is associated with considerable morbidity and mortality. The way in which the immune system responds to this treatment influences the occurrence of complications postoperatively, such as respiratory distress or sepsis, and subsequently impacts the rate of recovery and length of hospital stay.

This project aims to determine if there is a difference in how the immune system of obese patients reacts to treatment compared those who are not obese? And whether obesity increases the likelihood of complications and lengthen hospital stay? In order to investigate this:

  1. A full nutritional and anthropometrical assessment, including quantification of visceral fat area, is carried out on patients before and after chemoradiotherapy and surgery.
  2. Patients are also screened for the presence of the metabolic syndrome, a pro-inflammatory, pro-thrombotic state associated with excess visceral fat.
  3. Blood samples are obtained at baseline and at days 1, 3, 7 and 14 postoperatively and the individual immune cell types, including natural killer cells, macrophages and neutrophils are isolated. The amount and activity of the different cell types, i.e., what pro- or anti-inflammatory compounds are being secreted, is then assessed to determine the extent of the inflammatory response.
  4. Patients’ vital signs are recorded post surgery and any complications that occur are documented.
  5. Data will then be correlated with obesity, visceral adiposity and metabolic syndrome status to examine differences in innate immune responses and the occurrence of complications in obese versus non-obese patients.

On completion of this project, it is anticipated that our knowledge of how visceral obesity and the metabolic syndrome influence the innate inflammatory immune response post surgery and risk of postoperative complications will be greatly enhanced, possibly leading to the development of new therapies to reduce the high rates of morbidity and mortality associated with surgery for gastrointestinal cancers.

Exploring the association between visceral adipose tissue and gastrointestinal malignancy:
the role of the insulin-like growth factor pathway.

The aim of this study is to examine the insulin growth factor family and its role in the development of cancer in the oesophagus and colon. The insulin growth factor family is group of proteins involved in promoting growth and prolonging the life-span of cells within the body. People who are overweight and obese are more likely to develop certain cancers than those of normal body weight. They also have an increased risk of dying from cancer. Obese people produce increased amounts of insulin and the insulin-like growth factor family. We propose to look at differences in levels of these proteins between individuals with and those without cancer. Our theory is that the mechanism by which obese people have a higher risk of developing cancer of the colon and oesophagus is by increased activity of the insulin –like growth factor family. We will look for insulin-like growth factor receptor proteins in samples of tumour from patients with oesophageal and colorectal cancers and then specifically look at the influence of intra-abdominal fat on these levels in the blood and within the tumour.

Immune cells are the body’s mechanism of fighting off infection and repairing damaged tissue. They also help identify and kill cancer cells before they can organise themselves into a tumour. It is thought that belly fat causes immune cells in the body to become overactive so that obese people have immune cells which are overactive all of the time and cannot properly identify early cancer cells. We want to see whether insulin-like growth factors are produced by immune cells found in tumours.

We hope to determine whether the insulin growth factor family influences cancer growth and survival, reduces cancer cell death and enhances the ability of cancer cells to spread to other organs. If we can demonstrate that insulin-like growth factor is the reason why those who are overweight are at increased risk of developing cancer, there may be a role for blocking the action of insulin-like growth factor family to prevent or treat cancers in these patients

By establishing an improved scientific understanding of the link between obesity and cancer, we aim to provide scientific support for ongoing public health campaigns as well as hopefully providing valuable new insights into the mechanism of this association.

Delineating the pro-carcinogenic pathways activated in Barrett’s Oesophagus associated
with obesity and excess adiposity.

Oesophageal adenocarcinoma is one of the most deadly human malignancies. Barrett's oesophagus is the only known clinical predicator of oesophageal adenocarcinoma, patients with Barrett's oesophagus are up to 120 times more likely to develop adenocarcinoma of the oesophagus compared to the general population.

Barrett's oesophagus develops in patients when the squamous cells native to the oesophagus are damaged by prolonged gastro-oesophageal reflux disease (GORD), more commonly known as heartburn.

Sometimes, when the cells damaged by GORD heal, they regenerate as columnar intestinal like cells, cells which are generally found lower in the digestive tract, this process is an example of metaplasia.

A major risk factor for the development of Barrett's oesophagus, is obesity. Central obesity (the build up of fatty on the abdomen) causes increased pressure on the stomach, forcing the bile and gastric acids from the stomach up into the oesophagus, subsequently damaging the squamous cells there. While GORD may have an important role in the pathogenesis of Barrett’s disease, the acid alone is not severe enough to account for Barrett’s oesophagus. GORD is relatively common in both sexes and across all ethnicities, but the risk of developing Barrett’s oesophagus and the subsequent progression to oesophageal adenocarcinoma is far greater in men of Caucasian ethnicity compared to any other group, indicating that other factors besides GORD are involved.

Central obesity may also be involved in the development of Barrett’s oesophagus and the progression of oesophageal adenocarcinoma by other mechanisms, and this is the main aspect of my research. Adipose tissue, not only serves as long term energy storage, but is also metabolically active. Adipose tissue is rich in agents that regulate a host of physiological processes related to carcinogenesis. Abdominal fat, is more metabolically active that subcutaneous fat and this observation may partially explain the increase rates of Barrett's oesophagus in men, as abdominal obesity is more common in men than women.

My research involves culturing Barrett's oesophagus cells in vitro, in media generated from visceral fat removed from oesophageal adenocarcinoma patients (to mimic the affect of obesity) and then identifying changes in the gene expression of the Barrett's cells, and relating these changes in gene expression to carcinogenesis. Identifying these genes in Barrett's cells, and then studying these genes in Barrett's oesophagus biopsies from patients, may help elucidate the molecular mechanism by which obesity promotes the progression of Barrett’s oesophagus to oesophageal adenocarcinoma and identify novel therapeutic targets that may limit the progression of Barrett’s oesophagus to Oesophageal Adenocarcinoma.

The role of obesity in the development and progression of breast cancer:
Connecting epidemiology with molecular biology

Obesity is an increasingly recognised risk factor for breast cancer. Adipocytokines produced by local mammary adipose tissue (paracrine) as well as distant adipose deposits (endocrine) may be the mechanism by which obesity influences breast cancer. The aims of this research project is to determine the effect of obesity on gene expression of the adipocytokines leptin (Ob) and adiponectin (Adipo) in mammary adipose tissue, and their receptors (ObR, AdipoR1/R2) in tumour tissue. Breast cancer patients (n=40) undergoing surgery had anthropomorphic (Tanita BIanalyser, Waist circumference,BMI) and serological measurements of obesity/metabolic status (Glucose,Lipids,Insulin) performed. Matched adipose and tumour tissue were analysed using quantitative real time PCR for mRNA expression of a panel of genes: Ob,Adipo,ObR,AdipoR1/R2. In mammary adipose tissue, there was upregulation of Ob in obese women (p<0.05) relative to normal weight controls. Tumour samples expressed all three receptors. Expression of ObR was significantly increased in obese women compared to normal weight cancer patients (p<0.05). Serum leptin tended to positively correlate with ObR expression (r=0.4, p=0.055) while serum insulin, a marker of obesity and insulin resistance correlated strongly with ObR (r=0.58, p<0.005).There was no difference in tumour AdipoR1/R2 or gene expression compared to obesity status. Obesity status is associated with increased expression of the leptin gene in mammary adipose tissue and with increased leptin receptor expression in tumour tissue. ObR is also positively correlated with serum leptin and insulin. This association suggests this adipocytokine pathway regulates tumour biology. This may link the molecular association of obesity with breast cancer, highlighting potential targets for prevention and treatment strategies.

Identification of novel biomarkers of response to chemotherapy and chemoradiotherapy in oesophageal cancer

Oesophageal cancer is an aggressive disease with increasing annual incidence and an extremely poor prognosis.  Chemoradiotherapy (CRT) before surgery is the standard of care for oesophageal cancer patients. Unfortunately, only one third of patients have a good response to CRT, while the remaining patients receive little or no benefit. Indeed, evidence suggests that those patients who fail to respond to CRT ultimately have a worsened outcome due to the increased wait time to surgery as a result of receiving the CRT.

Presently, there are no reports describing microRNA studies to determine markers of resistance to therapy in this cancer. Studies to determine molecular predictors of response to chemoradiotherapy are essential to improve patient selection and ultimately therapeutic efficacy. In this proposal, we will examine, by microRNA microarray, the differential microRNA profiles in pre-treatment tumour samples from responder and non-responder patients receiving neoadjuvant chemoradiotherapy for oesophageal adenocarcinoma. Recent studies have shown that microRNAs are readily detected in plasma and serum. We shall also assess matched serum samples from these patients for the levels of differentially-expressed array-associated microRNAs, and critique it as a relatively non-invasive alternative to biopsy. The microRNA data will also be incorporated into a prediction model algorithm based on patient response to treatment, to establish the ‘microRNA signature’. We will validate the microRNA signature in an independent cohort of patients, and establish its positive and negative predictive values. Additionally, we will examine the combined power of both microRNA and gene expression profiles (previously published by this unit) in predicting patient response to therapy. Functionally, we will assess, using isogenic models of chemo- and radio-resistance, the relative contributions of specific signature microRNAs to tumour cell sensitivity to chemotherapeutics and radiation. This will be achieved via overexpression with pre-microRNA molecules. This work has important implications for oesophageal cancer therapy, in that the identification of microRNA signatures predictive of patient response to treatment will provide a platform for the development of a new diagnostic test. This may ultimately improve patient selection, treatment benefit, and survival. Moreover, understanding the contributions of microRNAs to therapeutic sensitivity may highlight new targets for future drug development.

The generation of an isogenic model of radioresistance to study the role of microRNAs
as biomarkers of response in oesophageal cancer

The standard treatment for oesophageal cancer employs a multimodal approach, whereby patients receive a course of chemotherapy and radiation therapy (CRT) to shrink their tumours and limit its spread to other sites, followed by surgery to remove the remaining tumour. Radiation therapy has played an important role in improving survival rates, however, tumour resistance to radiation remains a significant clinical problem. The elucidation of molecular mechanisms and markers of radioresistance would be of substantial benefit to cancer patients. We are working to identify biomarkers indicative of patient response to radiation therapy. This involves identifying genes and small non-coding RNA regulatory molecules, called microRNA, that are involved in the response to radiation and that play a role in conferring radioresistance to tumour cells. microRNAs are a relatively new discovery, and function to regulate genes within the cell. They play a vital role in important cellular processes such as cell survival and cell death, and mounting evidence also points to a role for these molecules in the response to radiation. We have developed a cell model of radioresistance in oesophageal adenocarcinoma and have identified several putative microRNA markers that are indicative of response to radiation. We are currently investigating the full functional role of these microRNA in radioresistance, and are assessing their potential as biomarkers of response to radiation, in both patient serum samples and tumour tissue samples from the departmental biobank. The data obtained in this project could ultimately be used in a diagnostic capacity to determine, prior to treatment, which patients are most likely to benefit from radiation therapy, facilitating individualisation of treatment. This work will also expand our knowledge of the critical mechanisms controlling tumour resistance to radiation therapy, and may identify novel molecular targets to enhance efficacy of radiation therapy.

Examining the role of the chemokine CCL28 across the Barrett’s
metaplasia-dysplasia-adenocarcinoma sequence in oesophageal cancer

The standard treatment for oesophageal cancer employs a multimodal approach, whereby patients receive a course of chemotherapy and radiation therapy (CRT) to shrink their tumours and limit its spread to other sites, followed by surgery to remove the remaining tumour. Radiation therapy has played an important role in improving survival rates, however, tumour resistance to radiation remains a significant clinical problem. The elucidation of molecular mechanisms and markers of radioresistance would be of substantial benefit to cancer patients. We are working to identify biomarkers indicative of patient response to radiation therapy. This involves identifying genes and small non-coding RNA regulatory molecules, called microRNA, that are involved in the response to radiation and that play a role in conferring radioresistance to tumour cells. microRNAs are a relatively new discovery, and function to regulate genes within the cell. They play a vital role in important cellular processes such as cell survival and cell death, and mounting evidence also points to a role for these molecules in the response to radiation. We have developed a cell model of radioresistance in oesophageal adenocarcinoma and have identified several putative microRNA markers that are indicative of response to radiation. We are currently investigating the full functional role of these microRNA in radioresistance, and are assessing their potential as biomarkers of response to radiation, in both patient serum samples and tumour tissue samples from the departmental biobank. The data obtained in this project could ultimately be used in a diagnostic capacity to determine, prior to treatment, which patients are most likely to benefit from radiation therapy, facilitating individualisation of treatment. This work will also expand our knowledge of the critical mechanisms controlling tumour resistance to radiation therapy, and may identify novel molecular targets to enhance efficacy of radiation therapy.

The role of COX, TXS and PGIS in NSCLC and Oesophageal Cancer

There is strong evidence to suggest that regular/occasional use of aspirin or other NSAIDs is inversely related to the risk of oesophageal cancer. One research area within the department is focused on examining the role of the molecular target of these NSAIDs, the cyclooxygenase (COX) signaling pathway, in oesophageal cancer. Epidemiological, experimental and early clinical evidence suggests that COX-2 is a potential molecular target for treatment and/or prevention of oesophageal cancer. However, chronic use of selective COX-2 inhibitors has been associated with unfavourable side effects, including cardiotoxicity. The tumour promoting effects of COX-2 may be mediated by downstream products of COX-metabolism, and targeting these pathways may provide therapeutic benefit while avoiding the adverse effects associated with COX-2 inhibition.

The respective roles of prostacyclin synthase (PGIS) and thromboxane synthase (TXS) (downstream enzymes of COX-metabolism) have been investigated in a variety of cancer states, including breast, prostate, thyroid, lung, colorectal and bladder cancer. While PGIS has been shown to protect against tumour development, thromboxane synthase has been implicated as a survival factor in many cancers, and has been associated with a poor prognosis. We are examining the interactions between these pathways, including platelet activation and thrombosis, apoptosis (programmed cell death) and angiogenesis (new blood vessel growth) in relation to their effects on tumour cell survival pathways.

Previous work carried out in our laboratory demonstrated TXS over-expression in non-small cell lung cancer (NSCLC) tumour samples, relative to matched normal controls. In contrast PGIS expression was reduced or lost in tumour samples, relative to matched controls. These findings implicate TXS as a potential survival factor in the disease, while PGIS may protect against tumour development. This hypothesis was supported by over-expression of these enzymes in a NSCLC cell line. While over-expression of PGIS inhibited tumour cell growth, increased apoptosis (programmed cell death) and reduced the invasiveness of the cells, over-expression of TXS resulted in directly opposing effects. While TXS and PGIS have been implicated in tumour survival and progression in a variety of cancers, little is known of the role of these enzymes in oesophageal cancer. Further studies in this area will examine the expression and relative contributions of these opposing enzymes in oesophageal cancer.

Thromboembolic disease following clinically disordered coagulation is among the most frequent haematological complications encountered by oncologists, affecting 15% of all cancer patients. It is also the second leading cause of death for cancer patients. The balance between PGI2 metabolite generation and platelet TXA2 synthesis is well known to influence thrombosis. PGIS and TXS will be therefore be examined in relation to thrombosis within the patients’ tumour, using both fresh and retrospective tissue and blood samples (from both NSCLC and oesophageal cancer). In addition, due to the well-known link between thrombosis and angiogenesis, the link between PGIS and TXS expression, and tumour angiogenesis will also be examined. This work is the first in its kind taking a translational approach to investigate expression of the TXS enzyme and the coagulation system in both lung and oesophageal cancer. Elucidation of the mechanisms regulating these pathways will potentially result in novel therapeutic strategies for intervention in these cancer states.