Abstract
The process of intravasation involving transendothelial migration is a key step in metastatic spread. How the triple cell complex composed of a macrophage, Mena over-expressing tumor cell and endothelial cell, called the tumor microenvironment of metastasis (TMEM), facilitates tumor cell transendothelial migration is not completely understood. Previous work has shown that the physical contact between a macrophage and tumor cell results in the formation of invadopodia, actin-rich matrix degrading protrusions, important for tumor cell invasion and transendothelial migration and tumor cell dissemination. Herein, we show that the macrophage-induced invadopodium is formed through a Notch1/MenaINV signaling pathway in the tumor cell upon macrophage contact. This heterotypic tumor cell – macrophage interaction results in the upregulation of MenaINV through the activation of MENA transcription. Notch1 and MenaINV expression are required for tumor cell transendothelial migration, a necessary step during intravasation. Inhibition of the Notch signaling pathway blocked macrophage-induced invadopodium formation in vitro and the dissemination of tumor cells from the primary tumor in vivo. Our findings indicate a novel role for Notch1 signaling in the regulation of MenaINV expression and transendothelial migration and provide mechanistic information essential to the use of therapeutic inhibitors of metastasis.
Highlights
Metastasis is the primary cause of morbidity and mortality of breast cancer patients
To evaluate if Notch signaling is required for macrophage – induced invadopodium formation (Fig. 1A), cells were treated with DAPT, a γ-secretase inhibitor, which inhibits intracellular Notch signaling by preventing its cleavage into the active NICD26
When BAC1.2F5 macrophages are added to the MDA-MB-231 culture there is a significant increase in the number of mature invadopodia per tumor cell but the addition of DAPT to these co-cultures prevents the macrophage-mediated induction of invadopodia (Fig. 1B)
Summary
Metastasis is the primary cause of morbidity and mortality of breast cancer patients. Each TMEM site is comprised of a Mena over-expressing tumor cell, a peri-vascular macrophage and an endothelial cell of a blood vessel in direct contact with each other. It is at these sites that transient vascular- permeability events and intravasation of breast tumor cells uniquely occur in breast tumors[2]. In addition to the macrophage-regulated vascular permeability events that contribute to tumor cell intravasation and metastasis, tumor cells form an invasive actin-rich invadopodium that enables the tumor cell to degrade extra-cellular matrix proteins and migrate, invading across barriers like blood vessel walls and intravasate[12,13,14]. Activation of Notch upon homotypic cell contact triggers invadopodium formation under hypoxia conditions[25]
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