CXCR7 mediates TGF beta 1-promoted EMT and tumor-initiating features in lung cancer

Abstract

In the tumor microenvironment, chemokine system has a critical role in tumorigenesis and metastasis. The acquisition of stem-like properties by cancer cells is involved in metastasis and drug resistance, which are pivotal problems that result in poor outcomes in patients with lung cancer. Patients with advanced lung cancer present high plasma levels of transforming growth factor-beta 1 (TGF beta 1), which correlate with poor prognostic features. Therefore, TGF beta 1 may be important in the tumor microenvironment, where chemokines are widely expressed. However, the role of chemokines in TGF beta 1-induced tumor progression still remains unclear. In our study, TGF beta 1 upregulated CXC chemokine receptor expression, migration, invasion, epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in lung adenocarcinoma. We found that CXCR7 was the most upregulated chemokine receptor induced by TGF beta 1. CXCR7 knockdown resulted in reduction of migration, invasion and EMT induced by TGF beta 1, whereas CXCR4 knockdown did not reverse TGF beta 1-promoted EMT. CXCR7 silencing significantly decreased cancer sphere-forming capacity, stem-like properties, chemoresistance and TGF beta 1-induced CSC tumor initiation in vivo. In clinical samples, high TGF beta 1 and CXCR7 expression was significantly associated with the late stages of lung adenocarcinoma. Moreover, TGF beta 1 and CXCR7 coexpression was positively correlated with the CSC marker, CD44, which is associated with lymph node metastasis. Besides, patients with high expression of both CXCR7 and TGF beta 1 presented a significantly worse survival rate. These results suggest that the TGF beta 1-CXCR7 axis may be a prognostic marker and may provide novel targets for combinational therapies to be used in the treatment of advanced lung cancer in the future.