The novel chemokine receptor CXCR7 regulates trans-endothelial migration of cancer cells

Brian A Zabel,Susanna Lewén,Thomas J Schall,Juan C Jaén,Robert D Berahovich

doi:10.1186/1476-4598-10-73

Brian A Zabel, Susanna Lewén + Show 3 more

Open Access

https://doi.org/10.1186/1476-4598-10-73

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Journal: Molecular Cancer	Publication Date: Jun 14, 2011
Citations: 133	License type: cc-by

Affiliation: ChemoCentryx (United States)

Abstract

BackgroundMigration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects.MethodsThe human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition.ResultsExposure of CXCR4+CXCR7+ cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4+CXCR7+ tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes.

Highlights

Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5
Chemokine receptor expression on NC-37 human B lymphoma cells includes CCR7 and CXCR5 To determine whether NC-37 cells are suitable to model CXCL12-mediated potentiation of CCL19 or CXCL13driven trans-endothelial migration (TEM) in lymph nodes, we evaluated chemokine receptor expression by these cells (Figure 1)
CXCL12 potentiates NC-37 cell TEM to CXCL13 In the TEM assay, NC-37 cells were tested for migration through a layer of human umbilical vein endothelial cells (HUVEC) into the bottom well of a 24-well chemotaxis plate, which contained CXCL13

Summary

Introduction

Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. CXCR4 regulates cancer metastasis to lymph node, bone, liver, and lung, the four most common metastatic destinations, which express high levels of CXCL12, the only known chemokine ligand for CXCR4 [3,4,5,6]. High levels of CXCL12 are present in the bloodstream [7,8,9,10]

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