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

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Abstract

Micro-Abstract

Identification of activated CXC-chemokine receptor 4 (CXCR4) in tumor biopsies would assist in selecting patients for potential CXCR4-targeted therapy. We analyzed 94 non–small-cell lung cancer (NSCLC) tissues by IHC of CXCR4 and its downstream signaling proteins as well as a mesenchymal transition (EMT) marker. We found that sub-cellular localization of CXCR4 was associated with its downstream signals and cytoplasmic CXCR4 correlated with EMT markers in NSCLC.

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 coreceptors for T-tropic human immunodeficiency virus entry into T cells. However, it 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 = .0015) and activation of ERK1/2 (P = .0121) and AKT (P = .0024), suggesting EMT in these tumors; whereas 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 biomarker changes associated with EMT in NSCLC.

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