Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro

Sarah J Storr,Stewart G Martin,Mohammed El-Refaee,Narmeen Ahmad,Andrew M Jackson,Sabreena Safuan

doi:10.1007/s00262-017-2020-0

Abstract

Lymphovascular invasion (LVI), encompassing blood and lymphatic vessel invasion, is an important event in tumourigenesis. Macrophages within the tumour microenvironment are linked to the presence of LVI and angiogenesis. This study investigates the role of macrophage-derived, caspase-1-dependent interleukin-1beta (IL-1β) in an in vitro model of LVI. IL-1β significantly augmented the adhesion and transmigration of breast cancer cell lines MCF7 and MDA-MB-231 across endothelial cell barriers. MDA-MB-231 and MCF7 showed a higher percentage of adhesion to lymphatic endothelial cells than blood endothelial cells following endothelial cell IL-1β stimulation (P < 0.001 and P < 0.0001, respectively). Supernatants from activated macrophages increased the adhesion of tumour cells to lymphatic and blood endothelium. Secretion of IL-1β was caspase-1 dependent, and treatment with caspase-1 inhibitor reduced IL-1β production by 73% and concomitantly reduced tumour cell adhesion to levels obtained with resting macrophages. Transmigration of MDA-MB-231 cells across blood and lymphatic endothelial monolayers was significantly increased following IL-1β stimulation. Furthermore, supernatants from activated macrophages increased transmigration of MDA-MB-231 cells across endothelial monolayers, which was abolished by caspase-1 inhibition. IL-1β stimulation of tumour cells significantly increased their migratory ability and a significant increase in migration was observed when MDA-MB-231 cells were stimulated with macrophage conditioned media (two of three donors). Results demonstrate that macrophage production of IL-1β plays an important role in the migration of breast cancer cells and their adhesion to, and transmigration across, blood and lymphatic endothelial cells. Results suggest that IL-1β may play a role in the adhesion to lymphatic endothelial cells in particular.

Highlights

Lymphovascular invasion (LVI), encompassing both blood and lymphatic vessel invasion, is an important event in tumourigenesis and is an initial prerequisite step in metastasis
This study aimed to investigate whether IL-1β can differentially modulate in vitro tumour cell adhesion and transmigration to, and across, blood and lymphatic endothelium and to assess its ability to alter tumour cell migration
The aims of this study were to determine the role of IL-1β on adhesion and transmigration to and across endothelial cell monolayers, and whether macrophage might be involved in this process

Summary

Introduction

Lymphovascular invasion (LVI), encompassing both blood and lymphatic vessel invasion, is an important event in tumourigenesis and is an initial prerequisite step in metastasis. Despite the link between immune cells within the tumour environment and the presence of LVI only a small number of factors have been identified that may have the ability promote vascular invasion, with most studies focussing upon factors that potentially influence blood vessel invasion. Cytokines are a loose category of small glycoproteins, including interleukins, interferons, chemokines and tumour necrosis factor (TNF). They are produced by a wide range of cells, notably immune cells and endothelial cells, fibroblasts, and various tumour and stromal cells. A number of cytokines, such as interleukin (IL)-8 and TNFα, are expressed at high levels by macrophages and can reportedly alter both angiogenesis and metastatic dissemination of tumour cells [9, 10]

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