Signal Transduction and Activator of Transcription-3 (STAT3) in Patients with Colorectal Cancer: Associations with the Phenotypic Features of the Tumor and Host.
Purpose:In patients with colorectal cancer, 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 IL6/JAK/STAT3 pathway. The present study examines the relationship between tumor total STAT3 and phosphorylated STAT3Tyr705(pSTAT3) expression, host inflammatory responses, and survival in patients undergoing resection of stage I-III colorectal cancer.Experimental Design:Immunohistochemical assessment of STAT3/pSTAT3 expression was performed using a tissue microarray and tumor 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:A total of 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 5-year survival from 81% to 62% (P= 0.012), however, was not associated with survival independent of venous invasion, tumor perforation, or tumor budding.Conclusions:In patients undergoing colorectal cancer resection, STAT3 expression was associated with adverse host inflammatory responses and reduced survival. Upregulation of tumor STAT3 may be an important mechanism whereby the tumor deregulates local and systemic inflammatory responses.Clin Cancer Res; 23(7); 1698-709. ©2016 AACR.
Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom. james.park@glasgow.ac.uk.|Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.
James H
JH
Park
Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom.
Hester
H
van Wyk
Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom.
Donald C
DC
McMillan
Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.
Jean
J
Quinn
Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.
Jennifer
J
Clark
Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom.
Campbell S D
CS
Roxburgh
Academic Unit of Surgery, School of Medicine, University of Glasgow, Royal Infirmary, Glasgow, United Kingdom.
Paul G
PG
Horgan
Unit of Experimental Therapeutics, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, United Kingdom.
Joanne
J
Edwards
D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007249:Inflammation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human