Non-Small Cell Lung Cancer Cells

Chemokines have been implicated as key contributors of non–small cell lung cancer (NSCLC) metastasis. However, the role of CXCR7,a recently discovered receptor for CXCL12 ligand, in the pathogenesis of NSCLC is unknown. To define the relative contribution of chemokine receptors to migration and metastasis, we generated humanlungA549andH157celllineswithstableknockdownofCXCR4,CXCR7,orboth.Cancercellsexhibited chemotaxis to CXCL12 that was enhanced under hypoxic conditions, associated with a parallel induction of CXCR4,butnotCXCR7.Interestingly,neitherknockdowncelllinedifferedintherateofproliferation,apoptosis, or cell adherence; however, in both cell lines, CXCL12-induced migration was abolished when CXCR4 signaling wasabrogated.Incontrast,inhibitionofCXCR7signalingdidnotaltercellularmigrationtoCXCL12.Inaninvivo heterotropic xenograft model using A549 cells, expression of CXCR4, but not CXCR7, on cancer cells was necessary for the development of metastases. In addition, cancer cells knocked down for CXCR4 (or both CXCR4 and CXCR7) produced larger and more vascular tumors as compared with wild-type or CXCR7 knockdown tumors, an effect that was attributable to cancer cell–derived CXCR4 out competing endothelial cells for available CXCL12 in the tumor microenvironment. These results indicate that CXCR4, not CXCR7, expression engages CXCL12 to mediate NSCLC metastatic behavior. Implications: Targeting CXCR4-mediated migration and metastasis may be a viable therapeutic option in NSCLC. Mol Cancer Res; 12(1); 38–47. � 2013 AACR.