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The role of COX, TXS and PGIS in NSCLC and Oesophageal Cancer

Dr. Mary Clare Cathcart, Postdoctoral Scientist
Dr. Mary Clare Cathcart, Postdoctoral Scientist

There is strong evidence to suggest that regular/occasional use of aspirin or other NSAIDs is inversely related to the risk of oesophageal cancer. One research area within the department is focused on examining the role of the molecular target of these NSAIDs, the cyclooxygenase (COX) signaling pathway, in oesophageal cancer. Epidemiological, experimental and early clinical evidence suggests that COX-2 is a potential molecular target for treatment and/or prevention of oesophageal cancer. However, chronic use of selective COX-2 inhibitors has been associated with unfavourable side effects, including cardiotoxicity. The tumour promoting effects of COX-2 may be mediated by downstream products of COX-metabolism, and targeting these pathways may provide therapeutic benefit while avoiding the adverse effects associated with COX-2 inhibition.

The respective roles of prostacyclin synthase (PGIS) and thromboxane synthase (TXS) (downstream enzymes of COX-metabolism) have been investigated in a variety of cancer states, including breast, prostate, thyroid, lung, colorectal and bladder cancer. While PGIS has been shown to protect against tumour development, thromboxane synthase has been implicated as a survival factor in many cancers, and has been associated with a poor prognosis. We are examining the interactions between these pathways, including platelet activation and thrombosis, apoptosis (programmed cell death) and angiogenesis (new blood vessel growth) in relation to their effects on tumour cell survival pathways.

Previous work carried out in our laboratory demonstrated TXS over-expression in non-small cell lung cancer (NSCLC) tumour samples, relative to matched normal controls. In contrast PGIS expression was reduced or lost in tumour samples, relative to matched controls. These findings implicate TXS as a potential survival factor in the disease, while PGIS may protect against tumour development. This hypothesis was supported by over-expression of these enzymes in a NSCLC cell line. While over-expression of PGIS inhibited tumour cell growth, increased apoptosis (programmed cell death) and reduced the invasiveness of the cells, over-expression of TXS resulted in directly opposing effects. While TXS and PGIS have been implicated in tumour survival and progression in a variety of cancers, little is known of the role of these enzymes in oesophageal cancer. Further studies in this area will examine the expression and relative contributions of these opposing enzymes in oesophageal cancer.

Thromboembolic disease following clinically disordered coagulation is among the most frequent haematological complications encountered by oncologists, affecting 15% of all cancer patients. It is also the second leading cause of death for cancer patients. The balance between PGI2 metabolite generation and platelet TXA2 synthesis is well known to influence thrombosis. PGIS and TXS will be therefore be examined in relation to thrombosis within the patients’ tumour, using both fresh and retrospective tissue and blood samples (from both NSCLC and oesophageal cancer). In addition, due to the well-known link between thrombosis and angiogenesis, the link between PGIS and TXS expression, and tumour angiogenesis will also be examined. This work is the first in its kind taking a translational approach to investigate expression of the TXS enzyme and the coagulation system in both lung and oesophageal cancer. Elucidation of the mechanisms regulating these pathways will potentially result in novel therapeutic strategies for intervention in these cancer states.

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Last updated 23 November 2016 Surgery - Web Administrator (Email).