Association of Cytoplasmic CXCR4 with Loss of Epithelial Marker and Activation of ERK1/2 and AKT Signaling Pathways in Non-Small Cell Lung Cancer

Abstract Objectives Compelling evidence demonstrates that CXC-chemokine receptor 4 (CXCR4) is involved in tumor invasion, angiogenesis, metastasis, and resistance to chemotherapy in addition to being one of the co-receptors for T-tropic HIV entry into T cells. However, it still remains controversial as to how to identify functionally activated CXCR4 in tumor biopsies, which would assist in determining which patients may benefit from potential CXCR4-targeted therapy. Materials and Methods Immunohistochemistry (IHC) staining on archival tissues of patients with non-small cell lung cancer (NSCLC) was used to detect a panel of biomarkers, including phospho-ERK1/2, phospho-AKT, and E-cadherin which are relevant to downstream signaling of CXCR4 and epithelial to mesenchymal transition (EMT). We also examined whether subcellular localization of CXCR4 could help define possible activation of CXCR4. Results A total of 94 primary tumor tissue samples from patients with NSCLC were included. Sixty-six patients had both cytomembranous and nuclear staining of CXCR4, 22 had solely nuclear staining, 5 had solely cytomembranous staining, and 1 had negative staining. Cytoplasmic location of CXCR4 with or without nuclear location was associated with loss of the epithelial marker E-cadherin ( p=0.0015 ) and activation of ERK1/2 ( p=0.0121 ) and AKT ( p=0.0024 ), suggesting Epithelial-mesenchymal transition (EMT) in these tumors; while tumors with only nuclear location of CXCR4 were more indolent and preserved an epithelial phenotype. Conclusions Our study suggests that different subcellular localization of CXCR4 may be associated with different activation states; cytoplasmic CXCR4 seems to correlate with biomarkers changes associated with EMT in NSCLC.