Cross, Neil - Sheffield Hallam University - Department of Biosciences and Chemistry

研究领域

1) Models of prostate cancer growth and survival 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. Role of cancer stem cells in tumour development Recent evidence suggests that tumour 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 ceases 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. The role of Nanog in prostate cancer stem cells These studies are investigating the role of the embryonic stem cell marker Nanog in the development of the cancer stem cell phenotype. Cancer stem cells are thought to be the 'root' of cancer, and selectively targeting these cells may have therapeutic implications. Using Nanog-reporter cell lines, we are isolating and characterising Nanog-positive cells from bulk populations, and assessing their phenotype. In vivo imaging of tumour growth in bone To directly visualise tumour metastasis to bone in experimental in vivo models, and to assess tumour colonisation within bone, Green Fluorescence Protein (GFP)-based imaging of tumours has been developed in collaboration with Dr Colby Eaton, University of Sheffield. Using GFP-transfected PC3 prostate cancer cells and a Lightools illumination system, tumours which are less than 1mm in diameter have been detected in the bone marrow cavity of live mice in our studies, allowing the study of early tumour-bone interactions. This technology has also been successfully applied to visualise tumour regression in response to treatment with anti-tumour agents, such as TRAIL, in live animals. These studies are in collaboration with Dr Colby Eaton, Academic Unit of Urology, University of Sheffield. 2) Molecular detection of Chlamydia trachomatis and its role in infertility Chlamydia trachomatis is one of the most prevalent sexually transmitted diseases, and is a major cause of infertility. Since it is an obligate intracellular pathogen, the culture and subsequent detection of viable Chlamydia is problematic. This is further complicated by persistent forms of the bacteria, (in response to antibiotics or endogenous interferon), which may be non-culturable but potentially viable. Earlier studies, in collaboration with Dr Adrian Eley (University of Sheffield) demonstrated to use of molecular detection of Chlamydial transcripts as an alternative to culture-based antimicrobial susceptibility testing. More recently, our studies, in collaboration with Dr Allan Pacey, Dr Adrian Eley and Professor Roy Jennings at The University of Sheffield, have used Real-Time PCR to quantify Chlamydia attachment to sperm in samples used for IVF, even after a washing procedure used to remove any bacteria present. Our ongoing studies are focused on developing methods for the study of 'persistent' forms of Chlamydia in vitro, and gene expression profiling for 'persistent' forms of Chlamydia.

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CHEN, Yu-Su, ALLEN, David, CROSS, Neil A, PITAK, Mateusz B, TIZZARD, Graham J, COLES, Simon J and BRICKLEBANK, Neil (2017). Biological and structural studies of phosphonium 'masked thiolate' compounds. European Journal of Medicinal Chemistry, 125, 528-537. HARVEY, Amanda, DAY, Rebecca, COLE, Laura M., BARTLETT, Maggie, WARWICK, John, BOJAR, Richard, SMITH, David, CROSS, Neil and CLENCH, Malcolm R. (2016). MALDI-MSI for the analysis of a 3D tissue-engineered psoriatic skin model. Proteomics, 16 (11-12), 1718-1725. MAHBUB, A.A., LE MAITRE, C.L., HAYWOOD-SMALL, S.L., CROSS, N.A. and JORDAN-MAHY, N. (2015). Glutathione is key to the synergistic enhancement of doxorubicin and etoposide by polyphenols in leukaemia cell lines. Cell Death and Disease, 6, e2028. MAHBUB, A.A., LE MAITRE, C.L., HAYWOOD-SMALL, S.L., CROSS, N.A. and JORDAN-MAHY, N. (2015). Polyphenols act synergistically with doxorubicin and etoposide in leukaemia cell lines. Cell Death Discovery, 1 (15043), 1-12. ZAINI, R, HAYWOOD-SMALL, S, CROSS, Neil and LE MAITRE, Christine (2015). Differential interactions of Falcarinol combined with anti-tumour agents on cellular proliferation and apoptosis in human lymphoid leukaemia cell lines. Journal of Blood Disorders and Transfusion, 6 (2).