Dr. Graham Pidgeon graduated from DCU with a degree in Analytical Science and obtained a Ph.D. in Cancer Research from the Dept. Surgery, RCSI/DCU in 2000. Awarded an American Cancer Foundation Fellowship, he worked as research fellow at Wayne State University, Michigan with Prof. Kenneth Honn on the regulation of prostate cancer survival by bioactive lipids. In 2002 he returned to Ireland as a senior postdoctoral fellow in the Dept. Clinical Pharmacology at RCSI. He was awarded a HRB postdoctoral fellowship in 2004, and joined Dr. Ken O'Byrne in the Thoracic Oncology Research Group at the Institute of Molecular Medicine at TCD/St. James as research lecturer. He developed his own research group focused on the regulation of VEGF-mediated survival pathways by COX and LOX in lung cancer and combining inhibitors of these pathways with conventional chemotherapy. He was appointed senior lecturer in Dept. Surgery at TCD/St.James in Jan 2007 and has expanded these research areas into other prevalent solid malignancies, including oesophageal cancer. He has published in a number of high impact journals including Cancer Research and Circulation, and was awarded the IJS doctor award 2005 for Cardiology. His current research is focused on the role of bioactive lipid enzymes including cycloxygenase and lipoxygenase in the growth and metastasis of lung and oesophageal cancer. Dr. Graham Pidgeon's group have a strong interest in the molecular processes regulating the growth and survival of oesophageal and lung cancer. Work in the past months has concentrated on the development of an adipose biobank from patients undergoing oesophageal and colorectal resections, to investigate the role of visceral fat in the progression of these malignancies. Recent scientific literature highlights the importance of central obesity and metabolic syndrome (MetS) as negatively impacting on cancer risk, tumour size, metastatic potential, and both disease free and overall survival. The group are prospectively investigating the incidence of central adiposity, metabolic syndrome and adipocyte secretion amongst newly diagnosed patients with these cancers to determine the link between these parameters and tumour size, metastases, treatment pathways, and survival.
Publications and Further Research Outputs
Moore G.Y, Pidgeon G.P, Cross-talk between cancer cells and the tumour microenvironment: The role of the 5-lipoxygenase pathway, International Journal of Molecular Sciences, 18, (2), 2017
Cathcart M.-C, Useckaite Z, Drakeford C, Semik V, Lysaght J, Gately K, O'Byrne K.J, Pidgeon G.P, Anti-cancer effects of baicalein in non-small cell lung cancer in-vitro and in-vivo, BMC Cancer, 16, (1), 2016, p707-
Mongan A.M, Lynam-Lennon N, Casey R, Maher S, Pidgeon G, Reynolds J.V, Oâ Sullivan J, Erratum to: Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma (Clin Transl Oncol, 10.1007/s12094-015-1411-y), Clinical and Translational Oncology, 18, (6), 2016, p651-
Malley CO, Pidgeon GP, The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials., BBA clinical, 5, 2016, p29-40
Mongan AM, Lynam-Lennon N, Casey R, Maher S, Pidgeon G, Reynolds JV, O'Sullivan J, Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma., Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 2015
Owusu Akuffo K, Nolan J, Stack J,Moran R, Feeney J,Kenny RA, Peto T, Dooley C, O'Halloran AM, Cronin C, and Beatty S. , Prevalence of age-related macular degeneration in the Republic of Ireland. , British Journal of Ophthalmology, 99, 2015, p1037-1044
Barr, M.P., Gray, S.G., Gately, K., (...), Pidgeon, G.P., O'Byrne, K.J., Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer, Molecular Cancer, 14, (1), 2015, p45-
Lynam-Lennon N, Connaughton R, Carr E, Mongan AM, O'Farrell NJ, Porter RK, Brennan L, Pidgeon GP, Lysaght J, Reynolds JV, O'Sullivan J., Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma., BMC Cancer, 3, (14), 2014, p907-
Howard JM, Cathcart MC, Healy L, Beddy P, Muldoon C, Pidgeon GP, Reynolds JV, Leptin and adiponectin receptor expression in oesophageal cancer., The British journal of surgery, 101, (6), 2014, p643-52
Lahiff C, Schilling C, Cathcart MC, Mulligan N, Doran P, Muldoon C, Murray D, Pidgeon GP, Reynolds JV, Macmathuna P, Prognostic significance of neuroepithelial transforming gene 1 in adenocarcinoma of the oesophagogastric junction., The British journal of surgery, 101, (2), 2014, p55-62
Lynam-Lennon N, Connaughton R, Carr E, Mongan AM, O'Farrell NJ, Porter RK, Brennan L, Pidgeon GP, Lysaght J, Reynolds JV, O'Sullivan J, Excess visceral adiposity induces alterations in mitochondrial function and energy metabolism in esophageal adenocarcinoma., BMC cancer, 14, 2014, p907
Cathcart MC, Gately K, Cummins R, Drakeford C, Kay EW, O'Byrne KJ, Pidgeon GP, Thromboxane synthase expression and correlation with VEGF and angiogenesis in non-small cell lung cancer., Biochimica et biophysica acta, 1842, (5), 2014, p747-55
Lahiff C, Cotter E, Casey R, Doran P, Pidgeon G, Reynolds J, Macmathuna P, Murray D, Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype., Journal of experimental & clinical cancer research : CR, 32, (1), 2013, p55
Allott EH, Lysaght J, Cathcart MC, Donohoe CL, Cummins R, McGarrigle SA, Kay E, Reynolds JV, Pidgeon GP, MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation., Molecular carcinogenesis, 52, (2), 2013, p144-54
Doyle SL, Bennett AM, Donohoe CL, Mongan AM, Howard JM, Lithander FE, Pidgeon GP, Reynolds JV, Lysaght J, Establishing computed tomography-defined visceral fat area thresholds for use in obesity-related cancer research., Nutrition research (New York, N.Y.), 33, (3), 2013, p171-9
Allott EH, Lysaght J, Cathcart MC, Donohoe CL, Cummins R, McGarrigle SA, Kay E, Reynolds JV, Pidgeon GP, MMP9 expression in oesophageal adenocarcinoma is upregulated with visceral obesity and is associated with poor tumour differentiation, Molecular Carcinogenesis, 2012
Allott EH, Morine MJ, Lysaght J, McGarrigle SA, Donohoe CL, Reynolds JV, Roche HM, Pidgeon GP, Elevated Tumor Expression of PAI-1 and SNAI2 in Obese Esophageal Adenocarcinoma Patients and Impact on Prognosis., Clinical and translational gastroenterology, 3, 2012, pe12
Allott EH, Oliver E, Lysaght J, Gray SG, Reynolds JV, Roche HM, Pidgeon GP, The SGBS cell strain as a model for the in vitro study of obesity and cancer., Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico, 14, (10), 2012, p774-82
Mary-Clare Cathcart, Kenneth J. O'Byrne, John V. Reynolds, Jacintha O' Sullivan, Graham P. Pidgeon, COX-Derived prostanoid pathways in gastrointestinal cancer development and progression: Novel targets for prevention and intervention, Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1825, (1), 2012, p49-63
SL Doyle, C Donohoe, S Finn, J Howard, FE Lithander, JV Reynolds, G Pidgeon, J Lysaght , IGF-1 and its Receptor in Esophageal Cancer: Association with Adenocarcinoma and Visceral Obesity, American Journal of Gastroenterology, 107, 2012, p196 - 204
Lynam-Lennon N, Reynolds JV, Marignol L, Sheils OM, Pidgeon GP, Maher SG, MicroRNA-31 modulates tumour sensitivity to radiation in oesophageal adenocarcinoma., Journal of molecular medicine (Berlin, Germany), 2012
Donohoe CL, Doyle SL, McGarrigle S, Cathcart MC, Daly E, O'Grady A, Lysaght J, Pidgeon GP, Reynolds JV., Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma, British Journal of Surgery, 99, (3), 2012, p387-96
Cathcart MC, Lysaght J, Pidgeon GP, Eicosanoid signalling pathways in the development and progression of colorectal cancer: novel approaches for prevention/intervention., Cancer metastasis reviews, 30, (3-4), 2011, p363-85
Carroll PA, Healy L, Lysaght J, Boyle T, Reynolds JV, Kennedy MJ, Pidgeon G, Connolly EM., Influence of the metabolic syndrome on leptin and leptin receptor in breast cancer., Molecular Carcinogenesis, 50, (8), 2011, p643 - 651
Lysaght J, Allott EH, Donohoe CL, Howard JM, Pidgeon GP, Reynolds JV., T lymphocyte activation in visceral adipose tissue of patients with oesophageal adenocarcinoma., British Journal of Surgery, 98, (7), 2011, p964 - 974
J. Lysaght, E.P. van der Stok, E.H. Allott, R. Casey, C.L. Donohoe, J.M. Howard, S.A. McGarrigle, N. Ravi, J.V. Reynolds, G.P. Pidgeon, Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue, Cancer Letters, 312, (1), 2011, p62-72
Lynam-Lennon N, Reynolds JV, Pidgeon GP, Lysaght J, Marignol L, Maher SG, Alterations in DNA repair efficiency are involved in the radioresistance of esophageal adenocarcinoma., Radiation research, 174, (6), 2010, p703 - 711
Howard JM, Beddy P, Ennis D, Keogan M, Pidgeon GP, Reynolds JV, Associations between leptin and adiponectin receptor upregulation, visceral obesity and tumour stage in oesophageal and junctional adenocarcinoma., The British journal of surgery, 97, (7), 2010, p1020-7
Howard JM, Pidgeon GP, Reynolds JV, Leptin and gastrointestinal malignancies , Obesity Reviews, 11, (12), 2010, p863-874
Mary-Clare Cathcart, John V. Reynolds, Kenneth J. O'Byrne, Graham P. Pidgeon, The role of prostacyclin synthase and thromboxane synthase signaling in the development and progression of cancer , Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1805, (2), 2010, p153-166
Byrne M, Reynolds JV, O'Donnell JS, Keogan M, White B, Byrne M, Murphy S, Maher SG, Pidgeon GP, Long-term activation of the pro-coagulant response after neoadjuvant chemoradiation and major cancer surgery., British Journal of Cancer, 102, (1), 2010, p73-9
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
Cryan LM, Pidgeon GP, Fitzgerald DJ, O'Brien CJ., COX-2 protects against thrombosis of the retinal vasculature in a mouse model of proliferative retinopathy., Molecular Vision, 12, (Apr 20), 2006, p405 - 414
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
M. Kandouz, D. Nie, G.P. Pidgeon, S. Krishnamoorthy, K.R. Maddipati, K.V. Honn., Platelet-type 12-lipoxygenase activates NF-kappaB in prostate cancer cells., Prostaglandins and Other Lipid Mediators, 71, (3-4), 2003, p189 - 204
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
G.P. Pidgeon, K. Tang, R.L. Rice, A. Zacharek, L. Li, J. D. Taylor, K.V. Honn., Overexpression of leukocyte-type 12-lipoxygenase promotes W256 tumor cell survival by enhancing alphavbeta5 expression., International Journal of Cancer, 105, (4), 2003, p459 - 471
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
G.P. Pidgeon, M.P. Barr, J.H. Harmey, D.A. Foley, D.J. Bouchier-Hayes, Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells, British Journal of Cancer, 85, (2), 2001, p273 - 278
G. P. Pidgeon, J. H. Harmey, E. Kay, M. Da Costa, H. P. Redmond and D. J. Bouchier-Hayes, The role of endotoxin/lipopolysaccharide in surgically induced tumour growth in a murine model of metastatic disease, British journal of cancer, 81, (8), 1999, p1311-7
DescriptionMy research interests focus on the regulation of vascular function and angiogenesis by bioactive lipids/prostanoids. Biologically active products derived from cyclooxygenase (COX) and lipoxygenase (LOX) mediated metabolism of arachidonic acid are involved in a range of clinical conditions, including arthritis, cancer and heart disease. One area of my research is in the examination of the role of the different COX isoforms, and their downstream products in pulmonary disease. There are reports that drugs which selectively inhibit COX-2 have detrimental effects on cardiac function, to date our results confirm that selective inhibition of COX-2 in models of hypoxia-induced pulmonary hypertension aggravates the problem. We are currently examining the mechanisms whereby cyclooxygenase isozymes regulate pulmonary hypertension and lung cancer, with an emphasis on COX-mediated angiogenesis and thrombosis in these diseases. A second area of research involves examining the role of bioactive lipids as survival factors in cancer. We are currently examining the role of 12-lipoxygenase, COX-2 and thromboxane synthase as survival factors in lung cancer and mesothelioma. The goal of this research is to identify the mechanisms whereby these enzymes facilitate tumour survival under conditions found within the tumour microenvironment, including hypoxia and serum deprivation. My third area of research interest is in the Vascular Endothelial Growth Factor receptors and their expression in lung cancer and mesothelioma. I am particularly interested in the Neuropilin family of receptors, their role in cell survival and regulation by bioactive lipids. We are currently examining the expression profile of VEGF receptors in cell lines and retrospective human lung cancers, to correlate their expression with tumour grade and stage.
- An investigation of the thromboxane and prostacyclin synthase pathways in non-small cell lung cancer.
- 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.
- Funding Agency
- Cancer Research Ireland
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- Neuropilin-1 expression and regulation by 12-Lipoxygenase in lung cancer.
- 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.
- Funding Agency
- Cancer Research Ireland
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- COX-isoforms and prostaglandins in an hypoxia-induced model of pulmonary hypertension.
- 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.
- Funding Agency
- Health Research Board
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Awards and Honours
Health Research Board PostDoctoral Fellowship
Cancer Research Foundation of America Research Fellowship
Honarary Fellow of the IBS (Institute of Biomedical Sciences), RCSI.
Member of the Irish Association of Cancer Research
Member of the American Association of Cancer Research