The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases

Am J Respir Crit Care Med. 2003 Jun 15;167(12):1676-86. doi: 10.1164/rccm.200301-071OC. Epub 2003 Mar 5.


Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12. CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor, and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / pathology*
  • Chemokine CXCL12
  • Chemokines, CXC / analysis*
  • Chemokines, CXC / antagonists & inhibitors
  • Chemokines, CXC / genetics
  • Disease Models, Animal*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Gene Expression Regulation, Neoplastic* / genetics
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / pathology*
  • Lymphatic Metastasis / pathology*
  • Mice
  • Mice, SCID
  • RNA, Neoplasm / analysis
  • RNA, Neoplasm / genetics
  • Receptors, CXCR4 / analysis*
  • Receptors, CXCR4 / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transplantation Chimera
  • Tumor Cells, Cultured


  • CXCL12 protein, human
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • RNA, Neoplasm
  • Receptors, CXCR4