Title: An In Vitro Vascularized Tumor Platform for Modeling Breast Tumor Stromal Interactions and Characterizing the Subsequent Response,
Abstract: Tumor stromal interactions have been shown to be the driving force behind the
poor prognosis associated with aggressive breast tumors. These interactions,
specifically between tumor and the surrounding ECM, and tumor and vascular
endothelium, promote tumor formation, angiogenesis, and metastasis. In this
study, we develop an in vitro vascularized tumor platform that allows for
investigation of tumor-stromal interactions in three breast tumor derived cell
lines of varying aggressiveness: MDA-IBC3, SUM149, and MDA-MB-231. The platform
recreates key features of breast tumors, including increased vascular
permeability, vessel sprouting, and ECM remodeling. Morphological and
quantitative analysis reveals differential effects from each tumor cell type on
endothelial coverage, permeability, expression of VEGF, and collagen
remodeling. Triple negative tumors, SUM149 and MDA-MB-321, resulted in a
significantly (p<0.05) higher endothelial permeability and decreased
endothelial coverage compared to the control TIME only platform. SUM149/TIME
platforms were 1.3 fold lower (p<0.05), and MDA-MB-231/TIME platforms were 1.5
fold lower (p<0.01) in endothelial coverage compared to the control TIME only
platform. HER2+ MDA-IBC3 tumor cells expressed high levels of VEGF (p<0.01) and
induced vessel sprouting. Vessels sprouting was tracked for 3 weeks and with
increasing time exhibited formation of multiple vessel sprouts that invaded
into the ECM and surrounded clusters of MDA-IBC3 cells. Both IBC cell lines,
SUM149 and MDA-IBC3, resulted in a collagen ECM with significantly greater
porosity with 1.6 and 1.1 fold higher compared to control, p<0.01. The breast
cancer in vitro vascularized platforms introduced in this paper are an
adaptable, high throughout tool for unearthing tumor-stromal mechanisms and
dynamics behind tumor progression and may prove essential in developing
effective targeted therapeutics.