Due to a highly malignant potential for lymph node metastasis and vascular invasion, long-term prognosis of esophageal carcinoma still is – despite curative surgery – poor with 5-year survival rates of 30% reported even recently 1. Squamous cell carcinoma and adenocarcinoma of the esophagus exhibit a different biological behaviour, pathogenesis and location, establishing the two tumor types as separate entities 23. Various studies have described the histologic differentiation as an independent prognostic factor after surgical R0-resection 45. Tumor spread, at least in advanced stages, in esophageal adenocarcinoma is characterized by distant metastases as compared to squamous cell carcinoma with a tendency towards local infiltrative growth 6.

Chemokines are a family of chemoattractant proteins that are classified depending on the arrangement of amino acids adjacent to conserved cysteine residues. CXCR4 is a seven-transmembrane G protein-coupled receptor and is also known as a coreceptor for HIV. SDF-1α (stem cell derived factor α), the natural ligand for CXCR4, is a member of the CXC chemokine family that has chemotactic activity for hematopoietic progenitor cells 78910. Thus far, chemokine signalling results in the transcription of target genes that are involved in cell invasion, motility, interactions with the extracellular matrix (ECM) and survival 11. The expression of the chemokine receptor CXCR4 has been shown to play key mechanisms in migration and metastasis with associated tumor progression and poor prognosis in a limited number of malignancies 12131415.

The role of chemokine receptors in tumor spread of esophageal cancer with a differentiated view of the two predominant histologic types yet has to be determined.

CXCR4 expression was detected in both types of esophageal cancer – squamous cell and adenocarcinoma. A slightly higher expression of CXCR4 (94.1% in squamous cell carcinoma and 89.1% in adenocarcinoma of the esophagus) was found as compared to other studies. Our data provide evidence that expression of CXCR4 by primary tumor cells is associated with malignant transformation in esophageal cancer, consistent with recent findings by Kaifi et al 17, but contrasted to a preceding investigation of Mitra et al., who used reverse transcriptase-polymerase chain reaction 18. The only study investigating CXCR4 expression in esophageal squamous cell and adenocarcinoma of the esophagus before- to our knowledge – has been published by Kaifi et al 17. Thus, the difference in the tumor-biologic behaviour of the two esophageal cancer types with a high incidence rate of locoregional spread in squamous cell carcinoma as compared to the development of distant metastasis in adenocarcinoma is not yet fully understood.

Although the exact mechanism of CXCR4 activity has not thoroughly been elucidated, it may induce or support carcinogenesis through the interaction of CXCR4 with its ligand SDF-1α, which mediates the activation of phosphatidylinositol 3-kinase and Akt, resulting in cell proliferation 1920. Interestingly, CXCR4 is regulated by different external factors, such as hypoxia (hif-1- pathway) and the activation of adenosine-receptors, as well as by internal alterations as the inactivation of tumor suppressor genes pVHL, p53, over-expression of NFkB and DNA methylation 2122232425. Homing factors, inducing chemotaxis to target organs of dissemination, have been proposed as the major inductor of tumour cell dissemination and metastatic growth, as the filter theory does not sufficiently explain the growth of metastases in target organs 262728. SDF-1α, which is produced elsewhere, is most intense in typical "homing organs" such as lungs, bone marrow, liver and lymph-nodes compared with other non-homing tissues 1417. The interaction between esophageal cancer-expressed CXCR4 and SDF-1α may be a key event in directing malignant cells to these "homing organs", and this mechanism may also account for metastasis from other organs, as previously reported 293031. This homing theory is underlined by the findings, that the presence of micrometastatic tumor cells in lymph nodes and bone marrow has been associated with poorer survival 3233.

In our study, the CXCR4 expression profile did not differ significantly between squamous cell carcinoma and adenocarcinoma in esophageal cancer, proposing additional factors responsible for their different patterns of tumor spread. It may also support the hypothesis of a similar pathway of CXCR4's influence on the lymphatic and hematogeneous tumor cell dissemination. Although the interaction of CXCR4 with the lymphatic system has not been investigated as intense as the hematogeneous dissemination, CXCR4 inhibition resulted in suppression of breast cancer lymph node metastases, implying common routes in both systems 34.

In both histologic types, strong CXCR4 expression revealed a poorer long-term prognosis following esophagectomy in curative intent. Thus, CXCR4 was not significantly associated with survival in contrast to a recent study by Kaifi et al, published in the Journal of the National Cancer Institute, 2005. Though a lack of statistical significance, there was a trend to a less favourable outcome associated with an increased intensity of CXCR4, as has previously been demonstrated for other malignancies 12131415. The histologic tumor type in the Cox regression analysis was statistically significant (p = 0.0001), which might be explained by the different biological behaviour associated with squamous cell and adenocarcinoma as published before (Gockel I, et al. World J Surg 2006;30:183–190) 6. Apart from the histologic tumor type, the pM-category proved an independent prognostic factor using Cox's proportional hazards model. Although all patients with pM1 (lymph) (= celiac trunk positive lymph node metastases) had undergone curative resection, this emphasizes the impact of systemic disease on impaired survival. The surgical procedure was another significant parameter in this analysis with a more favourable outcome following the transthoracic esophagectomy with extended lymphadenectomy, at least in patients with squamous cell carcinoma, as recently published 35.

Expression of the chemokine receptor CXCR4 in esophageal cancer is of major relevance in both histologic entities – squamous cell and adenocarcinoma. Though with lack of statistical significance, strong CXCR4 expression revealed a poorer long-term prognosis following curative esophagectomy in both histologic subtypes. The type of the surgical resection in esophageal cancer remained one of the most important factors with an influence on the patients' long-term prognosis.

Thus, the exact biological functions of CXCR4 in terms of tumor dissemination of esophageal cancer is yet undetermined. Inhibition of esophageal cancer progression by CXCR4 antagonists might be a promising therapeutic option in the future.

The author(s) declare that they have no competing interests.

I.G., C.C.S. and M.M. initiated the presented study, participated in its design and coordination and carried out the study. Before this specific study, C.C.S. and M.M. initiated other translational research projects on CXCR4 at the University of Mainz. C.H., T.W., D.D., C.v.L. and K.F. carried out the study. S.B. performed the histopathologic evaluation. M.D. carried out the statistical analysis. P.R.G. and T.J. participated in the coordination of the study. I.G. and C.C.S. drafted the first version of the manuscript and all authors read and approved the final manuscript.