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

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.

Reprogramming Tumor-Associated Macrophage Using Nanocarriers: New Perspectives to Halt Cancer Progression

“…MiR-23a-3p downregulated TJP1, occludin, and claudin 5, leading to increased vascular permeability. The phenomenon of increased vascular permeability in the presence of TAMs was also demonstrated in vitro in 3D system [44]: in the presence of TAMs, in particular M2, endothelium permeability increased 1.5-2 times in comparison with the vessel permeability in the absence of TAMs.…”

“…Co-culturing of endothelial cells and breast cancer cells with M2 macrophages were associated with increased vascular permeability, resulted from downregulated expression of intercellular junction protein PECAM-1 in the endothelial cells. Enhanced vascular sprouting resulted from increased levels of angiogenic factors, including TGF-β, bFGF, EGF, VEGF-A, IL-8, increased levels of MMP9 in culture medium which was associated with enhanced extracellular matrix porosity, and tumor emboli intravasation into the vessel [44].…”

The use of microphysiological systems to model metastatic cancer

“…However, this model lacked additional stromal or immune cell types. Therefore, Gadde et al further developed this model to include tumour associated macrophages [134]. After the inclusion of these macrophages there was an increase of ECM porosity, increased vascular sprouting and enhanced permeability of the endothelium.…”

“…The study was able to investigate the efficacy of anti-cancer drugs under dynamic flow conditions. Other template-based designs use a microneedle or rod to create simple single channel designed, an approach used by many of the MPS models that have been mentioned earlier in this review [33,76,77,133,134].…”