Mechanisms of Transendothelial Migration of Primary Human Invasive Ductal Carcinoma Cells from ER+, Her2+, and Triple-Negative Disease
Abstract
The primary cause of morbidity and mortality in breast cancer is distant metastases (1, 2). The direct contact between a breast tumor cell, macrophage, and endothelial cell, termed the Tumor MicroEnvironment of Metastasis or TMEM, correlated with metastasis in breast cancer patients independently of other clinical prognostic indictors (3-5). Here we show, using both primary cells directly from patients and breast cancer cell lines, that TMEM counts positively correlates with MenaINV mRNA expression regardless of receptor subtype. Tumor cells and macrophages participate in a paracrine signaling loop involving EGF and CSF secretion and their respective receptors (6-9). This paracrine signaling is required for efficient transendothelial migration of the tumor cells, a necessary step in the intravasation process. In addition, MenaINV expression also facilitates transendothelial migration of tumor cells (10). Furthermore, direct contact of a tumor cell and a macrophage drives the formation of mature invadopodia, protrusive structures that facilitate extracellular matrix degradation and have been shown to be necessary for transendothelial migration and thus intravasation (11). The direct contact between a macrophage and tumor cell results in the activation of Notch1 in the tumor cell. This Notch activity contributes to the invadopodia formation. These data considerably extend our understanding to the mechanisms of tumor cell transendothelial migration and thus intravasation into the blood, upon which cells can metastasize to secondary sites. It also further explores the mechanisms in which macrophages contribute to these processes. These results give us further insights into the prognostic value of TMEM as well as possible novel drug targets.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2015
- Accession Number
- AD1001755
Entities
People
- Jeanine Pignatelli
Organizations
- Albert Einstein College of Medicine