Abstract
Background
Chemokines are major regulators of cell trafficking and adhesion. The chemokine CXCL12 and its receptors, CXCR4 and CXCR7, have been reported as biomarkers in various cancers, including esophageal cancer; however, there are few studies in esophageal adenocarcinoma (EAC). In this study, we investigated the relationship between expression of CXCL12, CXCR4, and CXCR7, and prognosis in patients with EAC.
Methods
This study examined 55 patients with EAC who were treated in Toronto General Hospital from 2001 to 2010. Tissue microarray immunohistochemistry was used to evaluate the expression of CXCL12, CXCR4, and CXCR7. Evaluation of immunohistochemistry was performed by a pathologist without knowledge of patients’ information and results were compared with the patients’ clinicopathological features and survival.
Results
High CXCR7 expression was significantly associated with lymphatic invasion (present vs absent, P = 0.005) and higher number of lymph node metastases (pN0-1 vs pN2-3, P = 0.0014). Patients with high CXCR7 expression (n = 23) were associated with worse overall (OS) and disease-free survival (DFS) (P = 0.0221, P = 0.0090, respectively), and patients with high CXCL12 (n = 24) tended to have worse OS and DFS (P = 0.1091, P = 0.1477, respectively). High expression of both CXCR7 and CXCL12 was an independent prognostic factor for OS and DFS on multivariate analysis (HR = 0.3, 95% CI: 0.1–0.9, P = 0.0246, HR = 0.3, 95% CI: 0.1–0.8, P = 0.0134, respectively).
Conclusions
High CXCR7 expression was associated with poor prognosis in patients with EAC, and high expression of CXCR7 with its ligand CXCL12 had a stronger association with prognosis. Further study of this potential biomarker using whole tissue samples and a larger sample size is warranted.
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Acknowledgment
M. Liu is James and Mary Davie chair in lung injury, repair, and regeneration, supported by research grants from the Canadian Institutes of Health Research (MOP-42546, PJT-148847) and Government of Ontario Research Fund (RE-08-029).
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10434_2021_9775_MOESM3_ESM.pptx
Representative micrographs of cancer and normal tissues for immunohistochemistry staining. CXCL12 and CXCR7 were mainly stained in the cytoplasm and cellular membranes, and CXCR4 was mainly in nuclei (PPTX 20039 kb)
10434_2021_9775_MOESM4_ESM.pptx
Correlation between different staining. (A) CXCL12 and CXCR4, (B) CXCL12 and CXCR7, (C) CXCR4 and CXCR7. (B) The staining scores between CXCL12 and CXCR7 were positively correlated (r = 0.3154, P = 0.0308). A and B: Spearman’s correlation coefficient, C: Pearson’s correlation coefficient. VE: visual estimation (PPTX 108 kb)
10434_2021_9775_MOESM5_ESM.pptx
Evaluation of IHC staining using DIA software, HALO. (A) Original picture of tumor tissue stained with CXCL12, (B) staining intensity is digitalized and visually displayed by HALO, (C) evaluation criteria of staining intensity, (D) actual cell number of each staining intensity and final score. Red arrow shows the predominant intensity in this sample is 1+, accounting for 50.5% of total cells, and the final score of this sample is 3 (PPTX 812 kb)
10434_2021_9775_MOESM7_ESM.pptx
Correlation between visual estimation by pathologist and digital image analysis. (A) CXCL12, (B) CXCR4, (C) CXCR7. The scores of all three stains are significantly correlated, especially for CXCR7 expression. DIA: digital image analysis, VE-P: visual estimation by pathologist. Pearson’s correlation coefficient (PPTX 107 kb)
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Goto, M., Shibahara, Y., Baciu, C. et al. Prognostic Impact of CXCR7 and CXCL12 Expression in Patients with Esophageal Adenocarcinoma. Ann Surg Oncol 28, 4943–4951 (2021). https://doi.org/10.1245/s10434-021-09775-5
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DOI: https://doi.org/10.1245/s10434-021-09775-5