Abstract

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. CXCL12 is a key chemotactic factor for the trafficking of CLL. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. We aim to explore the role of TFPI in CXCL12-mediated migration of CLL cells. In this study, plasma TFPI concentrations were measured by ELISA. CLL cells were isolated from patients and used for trans-endothelial migration (TEM) assays. Quantitative RT-PCR and Western blotting were used to detect the expression of CXCR7, CXCR4 and β-catenin. Immunofluorescence and co-immunoprecipitation was used to detect the binding of TFPI and glypican-3 (GPC3). We found that plasma TFPI levels in CLL patients were higher than in healthy controls, particularly in the patients with advanced disease. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. The effect of TFPI on TEM was abolished by the CXCR7 inhibitor, CCX771, while the CXCR4 inhibitor AMD3100 strongly increased TEM. TFPI co-localized with GPC3 on the cell surface. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. TFPI activated β-catenin and the Wnt/β-catenin inhibitor IWP4 repressed the effect of TFPI on CXCR7 expression and TEM. We conclude that TFPI may contribute to organ infiltration in CLL patients.

Highlights

  • The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity

  • To understand how Tissue factor pathway inhibitor (TFPI) affects CXCL12-mediated trans-endothelial migration (TEM) of CLL cells, we investigated the expression of CXCR4 and CXCR7 in the CLL cells

  • TFPI was previously thought to be limited to its key role in regulating coagulation, but our data suggest that TFPI is involved in the migration of CLL cells

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Summary

Introduction

The infiltration of chronic lymphocytic leukemia (CLL) cells into lymphoid organs correlates with disease severity. Tissue factor pathway inhibitor (TFPI) is a serine protease inhibitor and plays a role in CXCL12-mediated hematopoietic stem cell homing. TFPI enhanced CXCL12-mediated TEM of CLL cells by increasing the expression of the CXCL12 receptor CXCR7, but not of the CXCL12 receptor CXCR4. An antibody to GPC3, HS20, decreased CXCR7 expression and abolished the effect of TFPI on TEM. CXCR7 has a stronger affinity for CXCL12 than C­ XCR410, and ligand binding to CXCR7 activates alternative signaling pathways regulating cellular adhesion, proliferation and dissemination of tumor ­cells[11] as well as differentiation of mature B ­cells[12]. CXCR7 has been shown to potentiate and regulate trans-endothelial migration (TEM) of circulating tumor cells leading to enhanced ­extravasation[13]. We have previously reported that TFPI is involved in cell migration in breast ­cancer[18]

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