Journal Article

TGF-β1-induced EMT promotes targeted migration of breast cancer cells through the lymphatic system by the activation of CCR7/CCL21-mediated chemotaxis

Tabor, V, Jansson, M, Lambut, L, Johansson, J, Betsholtz, C, Alexander, J S, Pang, M-F, Sund, M, Georgoudaki, A-M, Karlsson, M C I, Nelson, C M, Jin, Y, Jakobsson, L, Hagikura, K, Fuxe, J

2016

Overview

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial–mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14/35 / 631/67/1347 / 631/67/322 / 64/60 / 82/51 / 82/80 / Animals / Apoptosis / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Care and treatment / Cell Biology / Cell Movement - drug effects / Cell Movement - genetics / Cells, Cultured / Chemokine CCL21 - genetics / Chemokine CCL21 - metabolism / Chemotaxis - drug effects / Chemotaxis - genetics / Comparative analysis / Complications and side effects / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Female / Gene Expression Regulation, Neoplastic - drug effects / Human Genetics / Humans / Influence / Internal Medicine / Lymphatic Metastasis / Lymphatic System - drug effects / Lymphatic System - pathology / Medicine / Medicine & Public Health / Metastasis / Mice / Mice, Inbred BALB C / Neoplastic Cells, Circulating - drug effects / Neoplastic Cells, Circulating - metabolism / Neoplastic Cells, Circulating - pathology / Oncology / Original / original-article / p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors / Protein Kinase Inhibitors - pharmacology / Receptors, CCR7 - genetics / Receptors, CCR7 - metabolism / Risk factors / Stem cell research / Transforming Growth Factor beta1 - genetics / Transforming Growth Factor beta1 - physiology / Transforming growth factors