Apoptotic pathways in the progression to oesophageal adenocarcinoma: the role of Survivin Authors: Puccio I.1; Butt MA1, 2; Oukrif D4; Khan S 1; Haidry RJ.2, 1; Banks MR1,2; Novelli M2, 4;Lovat LB1, 2;Rodriguez-Justo M.2, 4 Institutions: 1. Translational Gastroenterology Group, National Medical Laser Centre, University College London 2. GI services, University College Hospital 3. UCL-Advanced Diagnostics, University College London 4. Research Department of Pathology, University College London, United Kingdom Contact: Ignazio Puccio BSc (Hons) MSc email:i.puccio@ucl.ac.uk Phone: +447544936972 Introduction Survivin is an inhibitor of apoptosis. It has been published that survivin is overexpressed in several human cancers but not in normal tissues. Inhibition of the apoptotic process is postulated to lead to the development of neoplastic clones with prolonged cell life. Survivin is integral to this process. Fig.1 Survivin inhibition pathway Aim To study the expression of Survivin (by immunohistochemistry) in the progression to oesophageal adenocarcinoma (OA) to gain an understanding of the stage at which the apoptotic pathway becomes important in this pathway. Method 1. Paraffin embedded specimens were selected from 50 patients containing normal squamous, normal gastric, non-dysplastic Barrett’s epithelium (BE), low grade dysplasia, carcinoma in-situ and invasive oesophageal adenocarcinoma. 2. Anti-Survivin antibody clone D-8 specific to the amino acids sequences 1-142 of the Survivin protein. 3. Intensity and extent of tissue staining was scored by 2 expert GI Pathologists, and mean scores calculated (one-way ANOVA and post-test analysis) 4. Correlations between groups were analysed with one-way ANOVA and post-test analysis) Results: IHC Nuclear expression of Survivin was typically noted, pattern of staining tissues For normal squamous tissue, expression was only noted in basal layers (Though normal tissues are postulated not to express Survivin, basal layer expression can be understood as these cells are perpetually recycling to maintain the squamous architecture) All other tissue types displayed a more uniform distribution. Fig.2 Survivin immunostained tissue- progression from BE to Cancer BE – LGD BE – HGD OA Both one-way analysis and post-test analysis show that all parameters correlated with pathological progression Conclusion Survivin expression is progressively up-regulated in the progression to oesophageal adenocarcinoma. Up-regulation occurs early and with increasing magnitude, suggesting increasingly prominent roles for apoptosis inhibition in this pathway. Inhibitors of Survivin may, potentially, play a role in the prevention progression as well as the treatment of oesophageal cancer. One-way analysis F R square P value Intensity  9.626  0.4611 <0.0001 Extent 11.54  0.5063  <0.0001 Allred  11.54  0.5064   0.0001 Post-analysis F R square P value Intensity  0.3194  0.3221  <0.0001 Extent 0.4558  0.3569 Allred 0.7753  0.3654 Proportion of cells staining positively Score Intensity of staining No cells Negative <1% 1 Weak 1-10% 2 Moderate 10-33% 3 Strong 33-66% 4   >66% 5 Acknowledgements This research was undertaken at UCL/UCH and funded by the DoH NIHR Biomedical Research Centres funding scheme and also by a grant from the UCL Experimental Cancer Medicine Centre, and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. It was done in collaboration with PhotoBiotics Ltd in Imperial College London. References 1 Li C et al. Plos One 2012;7(9):e44764. 2 Takeno S et al. Eur J Cardiothorac Surg.2010 Feb;37(2):440-5 3 Zhu H et al.Tumour Biol 2011 Dec;32(6):1147-53. 4 Chunguang Li et al. J. Plos One September 2012 | Volume 7 | Issue 9 | e44764 5 Malhotra U et al. J. Plos One. 2013 Nov 4;8(11):e78343. doi: 10.1371