In Vitro Vascularized Tumor Platform for Modeling Tumor-Vasculature
Interactions of Inflammatory Breast Cancer
Abstract
Inflammatory breast cancer (IBC), a rare form of breast cancer
associated with increased angiogenesis and metastasis, is largely driven
by tumor-stromal interactions with the vasculature and the extracellular
matrix (ECM). However, there is currently a lack of understanding of the
role these interactions play in initiation and progression of the
disease. In this study, we developed the first three-dimensional, in
vitro, vascularized, IBC platform to quantify the spatial and temporal
dynamics of tumor-vasculature and tumor-ECM interactions specific to
IBC. Platforms consisting of collagen type 1 ECM with an endothelialized
blood vessel were cultured with IBC cells, MDA-IBC3 (HER2+) or SUM149
(triple negative), and for comparison to non-IBC cells, MDA-MB-231
(triple negative). An acellular collagen platform with an endothelial
blood vessel served as control. SUM149 and MDA-MB-231 platforms
exhibited a significantly (p<0.05) higher vessel permeability
and decreased endothelial coverage of the vessel lumen compared to the
control. Both IBC platforms, MDA-IBC3 and SUM149, expressed higher
levels of VEGF (p<0.05) and increased collagen ECM porosity
compared to non-IBC MDA-MB-231 (p<0.05) and control
(p<0.01) platforms. Additionally, unique to the MDA-IBC3
platform, we observed progressive sprouting of the endothelium over time
resulting in viable vessels with lumen. The newly sprouted vessels
encircled clusters of MDA-IBC3 cells replicating a feature of in vivo
IBC. The IBC in vitro vascularized platforms introduced in this study
model well-described in vivo and clinical IBC phenotypes and provide an
adaptable, high throughout tool for systematically and quantitatively
investigating tumor-stromal mechanisms and dynamics of tumor
progression.