CD164 promotes lung tumor-initiating cells with stem cell activity and determines tumor growth and drug resistance via Akt/mTOR signaling

Abstract

CD164 is a cell adhesion molecule that increases hematopoietic stem cell proliferation, adhesion, and migration via C-X-C chemokine receptor type 4 (CXCR4) signaling. Emerging evidence indicates that elevated CD164 expression is associated with aggressive metastasis, advanced stages, and shorter overall survival in lung cancer. However, no data are available regarding the clinical significance of CD164 expression in lung cancer. This study explores whether CD164 promotes tumor-initiation and drug resistance through the stem cell property. Using tissue microarrays, we determine that CD164 expression is correlated with clinicopathological characteristics in human lung cancer. The CD164 overexpression in normal lung epithelial cells (BEAS2B cells) leads to malignant transformation in vitro, tumorigenicity in xenografted mice, stem cell-like property, and drug resistance through ATP-binding cassette transporters. The CD164 overexpression increases CXCR4 expression and activates Akt/mTOR signaling. Rapamycin, an mTOR inhibitor, hinders cell proliferation along with sphere formation in vitro and impedes tumor growth in vivo. In conclusion, we have provided evidence that CD164 promotes the growth of lung tumor-initiating cells with stem cell properties and induces tumor growth and drug resistance through Akt/mTOR signaling. Therefore, identification of CD164 as a cancer stem cell therapeutic marker may develop an effective therapy in patients with chemoresistant lung cancer.