Association with Survival of the CXCL12-CXCR4 Chemokine Axis in Adenocarcinoma of the Lung
P. L. Wagner1, M. Vazquez2, J. Port1, P. Lee1, A. Saqi2, N. Altorki1; 1Cardiothoracic Surgery, New York Presbyterian Hospital/Weill Cornell Medical Center, New York, NY; 2Pathology, Weill Cornell Medical College, New York, NY
Comment on this Abstract
Objective: Although the chemokine CXCL12 and its receptor, CXCR4, have been implicated in the metastatic potential of non-small cell lung carcinoma (NSCLC), the prognostic implications of these molecules are poorly defined. The aim of this study was to determine whether expression of these molecules correlates with differences in survival among patients with adenocarcinoma of the lung.
Methods: We examined 134 primary adenocarcinoma lesions resected from 101 patients, using immunohistochemical (IHC) staining intensity as a semi-quantitative measure of expression. Lesions were divided into high-expression or low-absent expression categories based on staining intensity. CXCL12 was detected in the cytoplasm and cell membrane but not in the nucleus; since CXCR4 was detected in the nucleus and cytoplasm, these two compartments were scored separately. Staining intensity was compared with clinicopathologic features including TNM stage and survival. Kaplan-Meier disease-free survival (DFS) curves were generated and compared using a log-rank test (significance, p<0.05).
Results: Significant differences in DFS were observed among lesions with respect to CXCR4 expression, depending upon the subcellular location of the molecule (see figure): nuclear expression was associated with improved survival, while cytoplasmic expression was associated with worse survival. Tumors with a high ratio of nuclear-to-cytoplasmic CXCR4 exhibited a particularly favorable prognosis (panel C of figure). These differences were observed among Stage I lesions, indicating that the association of CXCR4 expression with survival is stage-independent. Expression of CXCL12 did not correlate with survival.
Conclusion: Cytoplasmic expression of the chemokine receptor CXCR4 by lung adenocarcinomas is associated with poorer disease-free survival, whereas nuclear expression confers a survival benefit. These findings are consistent with a model in which CXCR4 promotes tumor progression when present in the cytoplasm or cell membrane, while localization of this molecule in the nucleus prevents it from exerting its effects associated with poorer survival. By contrast, expression of the chemokine ligand for this receptor, CXCL12, does not have significant prognostic implications.
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