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Prognostic Impact of CXCR7 and CXCL12 Expression in Patients with Esophageal Adenocarcinoma

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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).

Author information

Authors and Affiliations

  1. Department of Thoracic, Endocrine Surgery and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan

    Masakazu Goto MD, PhD

  2. Latner Thoracic Surgery Research Laboratories, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada

    Masakazu Goto MD, PhD, Yukiko Shibahara MD, PhD, Cristina Baciu PhD, Jonathan C. Yeung MD, PhD, Gail E. Darling MD & Mingyao Liu MD, MSc

  3. Department of Pathology, University Health Network, Toronto, Canada

    Yukiko Shibahara MD, PhD

  4. Division of Thoracic Surgery, Toronto General Hospital, University Health Network, Toronto, Canada

    Frances Allison BSc, Jonathan C. Yeung MD, PhD & Gail E. Darling MD

  5. Departments of Surgery, Medicine, and Physiology, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Mingyao Liu MD, MSc

Authors
  1. Masakazu Goto MD, PhD
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  2. Yukiko Shibahara MD, PhD
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  3. Cristina Baciu PhD
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  4. Frances Allison BSc
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  6. Gail E. Darling MD
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  7. Mingyao Liu MD, MSc
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Correspondence to Mingyao Liu MD, MSc.

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Supplementary file1 (DOCX 24 kb)

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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)

Examples of several other samples analyzed by DIA. Red Arrow shows predominant intensity in each sample (PPTX 2344 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

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