Led by Professor Nicola Woodroofe, the Disease Mechanisms Research Group carries out research into the molecular basis of several disease states. The group focuses on five themes. 

Cancer

Cancer is a genetic disease characterised 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. For example, 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.

Role of cancer stem cells in tumour development 

Recent evidence suggests that tumours consist 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 melanoma tissue and, if so, whether they can be selectively targeted by chemotherapeutic agents. 

The 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, as such, 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. 

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.  

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 deacetylase (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. 

Nutraceuticals in the prevention and treatment of cancer 

We are currently researching a number of novel compounds derived from fruit and vegetables. This involves 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. We have a particular interest in leukaemia, prostate cancer, gastrointestinal tract cancers and breast cancer.

Musculoskeletal disorders 

Arthritis 

Rheumatoid arthritis and osteoarthritis are two of the most common forms of arthritis. Rheumatoid arthritis is a chronic inflammatory disorder whereas inflammation in osteoarthritis tends to be associated mainly with its later stages. Both are associated with loss of articular cartilage producing joints which are painful on movement. 

Intervertebral disc degeneration 

Lower back pain is a major health problem affecting approximately 80% of the population at some time in their lives. 

Intervertebral disc degeneration has been implicated in approximately 40% of cases of low back pain and as such, is a promising therapeutic target. However, the current therapies are purely symptomatic or involve surgery, which does not address the initial causes of low back pain. 

Our studies investigate the pathogenesis of intervertebral disc degeneration, with the aim of developing new therapeutic approaches targeted at the abnormal cell biology which results in such degeneration. Particular interests include the role of cytokines and chemokines, and targeted therapies to intracellular signaling molecules, cannabinoids and the use of stem cells for regeneration approaches.  

Together with researchers in the Materials and Engineering Research Institute, Dr Le Maitre is working to develop a hydrogel delivery system for biological factors and mesenchymal stem cells to inhibit degeneration and induce regeneration.