| Angiogenesis |
Anticancer therapies |
Apoptosis |
Apoptosis, molecular control |
| Biological Markers |
Breast Cancer |
Breast cancer |
Cancer Biology |
| Cancer genetics and cell biology including metastasis |
Cancer/Carcinogenesis |
Cardiology |
Cardiovascular Diseases |
| Cardiovascular System |
Cardiovascular and molecular pharmacology |
Cardiovascular disease, pharmacology |
Cardiovascular regulation and hypertension |
| Cell Communication |
Cell Components |
Cell Lines |
Cell cycle control |
| Clinical research, trials |
Coronary artery ischaemia |
Cytoskelton, cell division |
DNA transcription and translation |
| Drug development and evaluation |
Extracellular Matrix |
Gene therapy |
Gene transcription in human cancer |
| Genomic structure and function, molecular approaches to gene function |
Growth Factors |
Immunology |
Inflammation and coagulation syndromes |
| Intra and intercellular signalling |
Lipids, steroids, membranes |
Lung Cancer |
Metabolism, Lipid |
| Molecular Biology |
Molecular Genetics |
Nutrition/Dietetics |
Oncogenes, apoptosis and tumour development |
| Oncology |
Pathogenesis |
Pathology |
Pharmacology |
| Platelet activating agents |
Prostaglandins |
Prostate Cancer |
Prostate cancer |
| Proteomics |
Pulmonary Diseases |
Radiotherapy, Biological response modifiers and chemoprevention |
Receptors |
| Regulatory methods of gene expression |
Respiratory System |
Therapeutic and Clinical oncology |
Thrombosis |
| Thrombosis and haemostasis |
Tissue Culture |
Transgenic Animals |
Tumour immunology and immunotherapy |
| Vascular Biology |
Vascular Biology, Thrombosis |
| Project title |
An investigation of the thromboxane and prostacyclin synthase pathways in non-small cell lung cancer. |
| Summary |
This research project will provide significant insights into the potential mechanisms whereby the balance between the expression of thromboxane synthase and prostacyclin synthase in lung cancer may confer a survival advantage on tumour cells directly. The series of experiments will examine the potential correlation between tumour expression of these PGH2 metabolising enzymes and clinical parameters, including thrombotic events, tumour angiogenesis and overall survival. These pathways have been implicated in various forms of malignancies and a number of specific inhibitors of TXS have shown promise in clinical trials, suggesting the translation of the research proposed here into future clinical applications in lung cancer should be rapid. The in vitro experiments are carefully designed to explore the potential survival mechanisms at the cellular protein level, by generating NSCLC clones with overexpression or silenced expression of these targets using molecular strategies. These clones will be thoroughly characterised both invitro and invivo for their effect on tumour cells. Direct clinical relevance will be highlighted by retrospectively examining the expression of TXS and PGIS expression in a series of resected lung tumours with varying stage and type of disease and also in frozen normal / tumour samples taken from the EU biobank at St. James Hospital.
By furthering our knowledge of these critical regulatory mechanisms controlling tumour cell survival, it is anticipated that new interventional therapies may be designed to target lung cancer, either alone or in combination with conventional radiotherapy and chemotherapy.
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| Funding Agency |
Cancer Research Ireland |
| Programme |
Project Grant Scheme |
| Type of Project |
Research - Post-doctoral |
| Date from |
2008 |
| Date to |
2011 |
| Person Months |
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| Project title |
Neuropilin-1 expression and regulation by 12-Lipoxygenase in lung cancer. |
| Summary |
This research project will provide significant insights into the potential mechanisms whereby neuropilin-1 expression in lung cancer may confer a survival advantage on tumour cells directly. The series of experiments will examine the potential correlation between tumour expression of the arachidonic acid metabolising enzyme 12-LOX and neuropilin-1 receptor expression in lung cancer. Each of these pathways have been implicated in various forms of malignancies and a number of specific inhibitors of LOX pathways have shown promise in clinical trials, suggesting the translation of the research proposed here into future clinical applications in lung cancer should be rapid. These experiments are carefully designed to explore the potential survival mechanisms at the cellular protein level, by overexpression of 12-LOX while targeting NRP-1 pathways by a neutralising or RNA silencing approach. Direct clinical relevance will be highlighted by retrospectively examining the expression of 12-LOX and NRP-1 expression in a series of resected lung tumours with varying stage and type of disease.
By furthering our knowledge of these critical regulatory mechanisms controlling tumour cell survival, it is anticipated that new interventional therapies may be designed to target lung cancer, either alone or in combination with conventional radiotherapy and chemotherapy.
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| Funding Agency |
Cancer Research Ireland |
| Programme |
Project Grants |
| Type of Project |
Research - PhD student |
| Date from |
2005 |
| Date to |
2008 |
| Person Months |
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| Project title |
COX-isoforms and prostaglandins in an hypoxia-induced model of pulmonary hypertension. |
| Summary |
Altered regulation of the cyclooxygenase (COX) signalling pathway underlies the development and progression of many diseases. The PGI2/TXA2 ratio is of particular importance in-vivo, with the corresponding synthases being shown to be differentially regulated. COX-derived prostanoids have been implicated in the development of PH, and an imbalance between the generation of thromboxane A2 (TXA2) and prostacyclin (PGI2) has been reported in both primary and secondary forms of the disease. These prostanoids have directly opposing effects; PGI2 is a potent vasodilator, is anti-proliferative, and inhibits platelet activation and aggregation, while TXA2 is a vasoconstrictor, is mitogenic and activates platelets and their aggregation. COX-2 is the main isoform responsible for the generation of PGI2, while TXA2 is mainly derived from platelets, where COX-1 is the main isoform. Exogenous PGI2 is effective in reducing pulmonary vascular resistance in some forms of human pulmonary hypertension (PH). To examine whether endogenous prostanoids played a similar role in PH, we examined the effect of deleting COX-gene isoforms in a chronic hypoxia model of the disease.
An experimental model of pulmonary hypertension (PH) was generated using COX-gene disrupted mice. PH was induced by 3 weeks of hypobaric hypoxia, and was confirmed by direct measurement of right ventricular end systolic pressure (RVESP), right ventricular hypertrophy (RVH) and increased haematocrit. RVESP was increased in wild-type (WT) hypoxic mice compared to normoxic controls, while COX-2 knock-out (KO) mice showed a further increase in RVESP following hypoxia. Urinary TXB2 excretion increased following hypoxia, an effect that was exacerbated following COX-2 gene disruption. In contrast, the increase in 6-keto-PGF1á excretion following hypoxia was reduced by COX-2 gene disruption. Tail-cut bleed times were reduced following hypoxia, and there was (immunohistochemical) evidence of intravascular thrombosis in lung vessels that was exacerbated by disruption of COX-2 and reduced by deletion of COX-1. The thromboxane receptor antagonist, ifetroban (50mg/kg/day) offset the effect of COX-2 gene deletion, by attenuating the hypoxia-induced rise in RVESP and intravascular thrombosis.
In addition to pulmonary vascular thrombosis, a second characteristic feature of pulmonary hypertension is the development of pulmonary vascular remodelling an angiogenesis. Real-time PCR analysis of vascular remodelling in the disease implicated a number of genes to be altered in the disease including VEGFC, EphB2, TNFá, TNFaip2, and CCl2. Genes of particular interest included VEGFC, EphB2, TNFá and TNFaip2, which are all pro-angiogenic factors that were down-regulated following COX-2 gene disruption. Further work is required to determine whether these changes in gene expression profile represent a beneficial or detrimental adaptation to chronic hypoxia exposure.
In conclusion, the findings of this research demonstrate that COX-2 gene deletion exacerbates the pathogenesis of pulmonary hypertension, enhances sensitivity to TXA2 and induces intravascular thrombosis in response to hypoxia. COX-2 gene deletion also down-regulated the expression of a number of angiogenic genes in response to hypoxia, suggesting that expression of these genes may have a beneficial effect in the pathogenesis of the disease. Our data provides evidence that endogenous prostanoids modulate the pulmonary response to hypoxia.
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| Funding Agency |
Health Research Board |
| Programme |
Post-doctoral Fellowship Scheme |
| Type of Project |
Research |
| Date from |
2004 |
| Date to |
2007 |
| Person Months |
36 |
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| Cathcart MC, Tamosiuniene R, Chen G, Neilan TG, Bradford A, O' Byrne KJ, Fitzgerald DJ, Pidgeon GP., COX-2-Linked Attenuation of Hypoxia-Induced Pulmonary Hypertension and Intravascular Thrombosis., Journal of Pharmacology and Expreimental Therapeutics, 2008 |
| Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, O'Byrne K, Nie D, Honn KV., Lipoxygenase metabolism: roles in tumor progression and survival., Cancer Metastasis Reviews, 3-4, 2007, p503 - 524 |
G.P. Pidgeon, R. Tamosiuniene, G. Chen, I. Leonard, O. Belton, A. Bradford, D.J. Fitzgerald, Intravascular thrombosis after hypoxia-induced pulmonary hypertension: regulation by cyclooxygenase-2., Circulation, 110, (17), 2004, p2701 - 2707
Url |
G.P. Pidgeon, K. Tang, Y.L. Cai, E. Piasentin, K.V. Honn., Overexpression of platelet-type 12-lipoxygenase promotes tumor cell survival by enhancing alpha(v)beta(3) and alpha(v)beta(5) integrin expression., Cancer Research, 63, (14), 2003, p4258 - 4267 TARA - Full Text
DOI |
G.P. Pidgeon, M. Kandouz, A. Meram, K.V. Honn., Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells., Cancer Research, 62, (9), 2002, p2721 - 2727
Url TARA - Full Text |
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