Disease mechanisms
Cancer
Cancer
is a genetic disease characterized by excessive cell proliferation, migration
and invasion, which result in tumour development and its subsequent spreading
to other tissues and organs. Phenotypic alterations in cell morphology and
function are underlined by changes in gene/protein structure and expression.
Expression of many other proteins is aberrant; either elevated or reduced
e.g. expression of matrix metalloproteinases is increased resulting in modifications
in extracellular matrix. This facilitates release of cancer cells from the
tumour and their spreading.
Many currently developed anti-cancer therapies exploit knowledge of the fundamental molecular and cellular mechanisms involved in tumour formation and progression, including changes in the function and expression of the crucial proteins.
Improving the understanding of tumour development
Role of cancer stem cells in tumour development
Recent evidence suggests that tumours comprise of differentiated tumour cells, which have a limited life-span, and cancer stem cells/tumour initiating cells, which are undifferentiated cells with unlimited replicative ability and the ability to differentiate. The cancer stem cells hypothesis suggests that if cancer stem cells are selectively ablated, tumour growth will cease and eventually the tumour will regress. In this study, we are investigating whether cancer stem cells are present in primary uveal melamona tissue, and if present, whether they can be selectively targeted by chemotherapeutic agents. This study is based on our observations that 'primitive' tumourigenic sub-populations of cells with no cytogenetic aberrations are present in uveal melanoma tumours, in contrast to the majority of the cells within the tumour. These cytogenetically 'normal' tumour cells may represent cells at the earliest stage in tumour development and hence, may represent the cancer stem cell population in uveal melanoma. Related studies on prostate cancer are also addressing the cancer stem cell hypothesis. These studies are in collaboration with Dr Karen Sisley, University of Sheffield.
Studies are led by Dr Neil Cross.
TMPRSS2:ERG fusion gene in prostate cancer
The majority of prostate cancers have a recurrent translocation involving the Ets-related gene/ERG oncogene and the androgen-responsive promoter of the TMPRSS2 gene, resulting in androgen-driven ERG expression. Although androgen-driven oncogene expression should represent an Achilles' heel for prostate cancer, since primary treatment of prostate cancer is by androgen withdrawal, this is not the case. Using cell lines that express this fusion gene, studies are aimed at investigating how androgen withdrawal affects ERG expression, and how cancer cells ultimately bypass ERG silencing in the absence of androgens.
These studies are in collaboration with Dr Colby Eaton, Academic Unit of Urology, University of Sheffield.
Studies are led by Dr Neil Cross.
MUC-gene expression in metastasis liver cancer
The presence of mucus is common in metastastic liver cancer and is believed to be indicative of a poor prognosis. In order to test this hypothesis and determine whether MUC-gene expression and mucin production can be used as a prognostic marker, a retrospective study is being undertaken of MUC-gene expression and mucin production in paired primary colorectal adenocarcinomas and secondary liver cancer tumours.
Studies are led by Dr Nikki Jordan-Mahy.
Developing novel therapies to cancer
Factors regulating the activity of the anti-tumour agent TRAIL
Recent studies have focused on how tumours evade apoptotic signals from Tumour Necrosis Factor (TNF) superfamily members, with particular emphasis on the potential anti-tumour agent TRAIL (TNF-Related Apoptosis Inducing Ligand), its receptors (Death Receptors 4 and 5) and decoy receptors (Decoy receptors 1 and 2, and OPG (Osteoprotegerin). Current studies are focusing on mechanisms of TRAIL resistance in cancer cells, and whether combinations of agents such as histone deactylase (HDAC) inhibitors, nuclear export inhibitors and proteasome inhibitors can reverse TRAIL resistance. In our recent studies, we have also demonstrated that nuclear export inhibitors in particular can potently enhance tumour cell sensitivity to TRAIL in a range of tumour cells.
Studies are led by Dr Neil Cross.
Nutraceuticals in the prevention and treatment of cancer
Researchers within the Biomedical Research Centre are currently researching a number of novel compounds derived from fruit and vegetables. The group is currently investigating the biological effects on tumour and non-tumour cells of agents derived from carrots, pomegranates, rhubarb, beetroot, cabbage and broccoli. Specifically we are interested in their potential to induce cell death and inhibit proliferation and the molecular mechanisms of their actions. The group has particular interest in leukaemia, prostate cancer, gastrointestinal tract cancers and breast cancer.
These studies are led by Dr Christine Le Maitre, Dr Nikki Jordan-Mahy and Dr Neil Cross.
Protease targeted therapies
The design of novel approaches to very specific killing of cancer cells based on the conversion of inactive pro-drugs into active drugs by proteases produced by cancer cells are led by Dr Wjasschesslaw Wlassoff.
