1. 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 Phone:
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 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  
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):
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):e doi: