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 journalArticlepeer-review

121 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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