CXCR4 Enhances Adhesion of B16 Tumor Cells to Endothelial Cells in Vitro and in Vivo via β1 Integrin

Adela R. Cardones, Takashi Murakami, Samuel T Hwang

Research output: Contribution to journalArticle

120 Scopus citations

Abstract

The chemokine receptor, CXCR4, is expressed by human melanomas, and its ligand, CXCL12, is frequently produced at sites of melanoma metastasis. Herein, we examine CXCR4-enhanced binding of B16 murine melanoma cells to endothelial cells (ECs) and recombinant adhesion molecules in vitro to determine the role of tumor- and EC-derived adhesion molecules in tumor metastasis. By flow cytometry, unstimulated primary lung ECs showed constitutive expression of vascular cellular adhesion molecule 1 (VCAM-1), whereas skin-derived ECs did not. All B16 cell lines tested showed constitutive expression of α 4 and β1 integrin chains but showed no expression β2 integrins. CXCR4-B16 arrest on VCAM-1/immunoglobulin-coated plates and tumor necrosis factor α-stimulated ECs under physiological shear stress conditions (1.5 dynes/cm2) was rapid, resistant to shear stress of 10 dynes/cm2, and showed no evidence of rolling before arrest. In vitro, CXCR4-B16 cell binding to ECs was blocked by anti-β1 and anti-CXCL12 monoclonal antibodies. In vivo, metastasis of CXCR4-B16 cells to murine lungs was strongly inhibited by anti-CXCL12 and two different anti-β1 monoclonal antibodies. Finally, CXCR4-B16 exposed to CXCL12 rapidly increased binding affinity for soluble VCAM-1/immunoglobulin as detected by a flow cytometric assay. Thus, β1 integrins play a critical role in CXCR4-mediated B16 tumor cell metastasis in vivo and may be a potential target for inhibition of tumor metastasis, particularly to the lung.

Original languageEnglish (US)
Pages (from-to)6751-6757
Number of pages7
JournalCancer Research
Volume63
Issue number20
StatePublished - Oct 15 2003
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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