Abstract
Purpose: Barrett's esophagus represents an early stage in carcinogenesis leading to esophageal adenocarcinoma. Considerable evidence supports a major role for chronic inflammation and diverse chemokine pathways in the development of Barrett's esophagus and esophageal adenocarcinoma.Experimental Design: Here we utilized an IL1β transgenic mouse model of Barrett's esophagus and esophageal adenocarcinoma and human patient imaging to analyze the importance of CXCR4-expressing cells during esophageal carcinogenesis.Results: IL1β overexpression induces chronic esophageal inflammation and recapitulates the progression to Barrett's esophagus and esophageal adenocarcinoma. CXCR4 expression is increased in both epithelial and immune cells during disease progression in pL2-IL1β mice and also elevated in esophageal adenocarcinoma patient biopsy samples. Specific recruitment of CXCR4-positive (CXCR4+) immune cells correlated with dysplasia progression, suggesting that this immune population may be a key contributor to esophageal carcinogenesis. Similarly, with progression to dysplasia, there were increased numbers of CXCR4+ columnar epithelial cells at the squamocolumnar junction (SCJ). These findings were supported by stronger CXCR4-related signal intensity in ex vivo fluorescence imaging and autoradiography with advanced dysplasia. Pilot CXCR4-directed PET/CT imaging studies in patients with esophageal cancer demonstrate the potential utility of CXCR4 imaging for the diagnosis and staging of esophageal cancer.Conclusion: In conclusion, the recruitment of CXCR4+ immune cells and expansion of CXCR4+ epithelial cells in esophageal dysplasia and cancer highlight the potential of CXCR4 as a biomarker and molecular target for diagnostic imaging of the tumor microenvironment in esophageal adenocarcinoma. Clin Cancer Res; 24(5); 1048-61. ©2017 AACR.
Highlights
The chemokine receptor 4 (CXCR4) has been shown to be consistently overexpressed in a variety of solid tumors [1,2,3]
We utilized our transgenic mouse model of Barrett's esophagus and dysplasia to analyze the pattern of CXCR4 expression during esophageal carcinogenesis [19]. pL2-IL1b mice
When pL2-IL1b mice were fed a high-fat diet (HFD), they develop accelerated disease, with mid-grade dysplastic lesions along the squamocolumnar junction (SCJ) by 9 months and larger highgrade dysplastic lesions in the esophagus and SCJ at 12 months (Fig. 1A, i and ii), enabling us to study changes associated with stepwise progression of esophageal carcinogenesis
Summary
The chemokine receptor 4 (CXCR4) has been shown to be consistently overexpressed in a variety of solid tumors [1,2,3]. CXCR4 overexpression promotes tumor invasiveness and metastasis by facilitating retention and homing of tumor cells in cellular niches such as the bone marrow. Expression of CXCR4 by hematopoietic progenitor cells (HPCs) and the production of CXCL12 by stromal cells and osteoblasts are important for homing and retention of these cells. Together with other cytokines (e.g., SCF and IL7), CXCR4 function is required for normal maturation of myeloid and lymphoid cells, and for the survival and proliferation of B-cell precursors and myeloid progenitor cells [10]. While CXCR4 has been shown to be expressed by columnar epithelial cells in the gastrointestinal tract, where it appears to mark progenitors, the role of CXCR4 signaling in this setting remains to be elucidated [11]
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