Influence of Macrophages on Vascular Invasion of Inflammatory Breast Cancer Emboli Measured Using an In Vitro Microfluidic Multi-Cellular Platform

SIMPLE SUMMARY: Macrophages, specifically tumor-associated macrophages (TAMs), play a vital role in inflammatory breast cancer (IBC) progression, including cell growth, angiogenesis, and resistance to treatment. Current in vitro models for studying IBC have limitations and do not fully capture the dynamic nature of interactions between macrophages, the tumor, and the microenvironment in IBC. Therefore, we have developed a 3D in vitro model of IBC that incorporates a collagen matrix, functional blood vessels, and THP1 M0, M1, or M2 macrophages, allowing for the study of macrophage-tumor interactions and angiogenesis. Using this platform, it was found that Incorporating TAMs increases the number of new vessel sprouts, permeability of the vessel, matrix porosity, and intravasation of MDA-IBC3 cells. Additionally, IL8 and MMP-9, which are known to promote angiogenesis and tumor invasion, were found to be preferentially secreted in M0 and M2 co-culture platforms. ABSTRACT: Inflammatory breast cancer (IBC) is an aggressive disease with a poor prognosis and a lack of effective treatments. It is widely established that understanding the interactions between tumor-associated macrophages (TAMs) and the tumor microenvironment is essential for identifying distinct targeting markers that help with prognosis and subsequent development of effective treatments. In this study, we present a 3D in vitro microfluidic IBC platform consisting of THP1 M0, M1, or M2 macrophages, IBC cells, and endothelial cells. The platform comprises a collagen matrix that includes an endothelialized vessel, creating a physiologically relevant environment for cellular interactions. Through the utilization of this platform, it was discovered that the inclusion of tumor-associated macrophages (TAMs) led to an increase in the formation of new blood vessel sprouts and enhanced permeability of the endothelium, regardless of the macrophage phenotype. Interestingly, the platforms containing THP-1 M1 or M2 macrophages exhibited significantly greater porosity in the collagen extracellular matrix (ECM) compared to the platforms containing THP-1 M0 and the MDA-IBC3 cells alone. Cytokine analysis revealed that IL-8 and MMP9 showed selective increases when macrophages were cultured in the platforms. Notably, intravasation of tumor cells into the vessels was observed exclusively in the platform containing MDA-IBC3 and M0 macrophages.