Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host

Park, J. H. , Van Wyk, H. C., McMillan, D. C. , Quinn, J. A. , Clark, J., Roxburgh, C. , Horgan, P. G. and Edwards, J. (2017) Signal transduction and activator of transcription-3 (STAT3) in patients with colorectal cancer: associations with the phenotypic features of the tumour and host. Clinical Cancer Research, 23(7), pp. 1698-1709. (doi: 10.1158/1078-0432.CCR-16-1416) (PMID:27678454)

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Purpose: In patients with colorectal cancer (CRC), a high-density local inflammatory infiltrate response is associated with improved survival, whereas elevated systemic inflammatory responses are associated with poor survival. One potential unifying mechanism is the IL-6/JAK/STAT3 pathway. The present study examines the relationship between tumour total STAT3 and phosphorylated STAT3Tyr705 (pSTAT3) expression, host inflammatory responses and survival in patients undergoing resection of stage I-III CRC. Experimental Design: Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumour cell expression divided into tertiles using the weighted histoscore. The relationship between STAT3/pSTAT3 expression and local inflammatory (CD3+, CD8+, CD45R0+, FOXP3+ T-cell density and Klintrup-Mäkinen grade) and systemic inflammatory responses and cancer-specific survival were examined. Results: 196 patients were included in the analysis. Cytoplasmic and nuclear STAT3 expression strongly correlated (r=0.363, P<0.001); nuclear STAT3 and pSTAT3 expression weakly correlated (r=0.130, P=0.068). Cytoplasmic STAT3 was inversely associated with the density of CD3+ (P=0.012), CD8+ (P=0.003) and FOXP3+ T-lymphocytes (P=0.002) within the cancer cell nests and was associated with an elevated systemic inflammatory response as measured by modified Glasgow Prognostic Score (mGPS2: 19% vs. 4%, P=0.004). The combination of nuclear STAT3/pSTAT3 stratified five-year survival from 81% to 62% (P=0.012), however was not associated with survival independent of venous invasion, tumour perforation or tumour budding. Conclusion In patients undergoing CRC resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Up-regulation of tumour STAT3 may be an important mechanism whereby the tumour deregulates local and systemic inflammatory responses.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Park, Mr James and Horgan, Professor Paul and Clark, Dr Jennifer and Roxburgh, Professor Campbell and Quinn, Dr Jean and Edwards, Professor Joanne and McMillan, Professor Donald
Authors: Park, J. H., Van Wyk, H. C., McMillan, D. C., Quinn, J. A., Clark, J., Roxburgh, C., Horgan, P. G., and Edwards, J.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1557-3265
Published Online:27 September 2016
Copyright Holders:Copyright © 2017 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 23(7):1698
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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