Abstract
BackgroundInteractions between cancer cells and stroma are critical for growth and invasiveness of epithelial tumors. The biochemical mechanisms behind tumor-stromal interactions leading to increased invasiveness and metastasis are mostly unknown. The goal of this study was to analyze the direct effects of staged stroma-derived extracellular matrices on breast cancer cell behavior.MethodsEarly and late three-dimensional matrices were produced by NIH-3T3 and tumor-associated murine fibroblasts, respectively. After removing fibroblasts, extracted matrices were re-cultured with breast epithelial cells of assorted characteristics: MCF-10A (non-tumorigenic), MCF-7 (tumorigenic, non-invasive), and MDA-MB-231 (tumorigenic, invasive). Effects prompted by staged matrices on epithelial cell's growth, morphology and invasion were determined. Also, matrix-induced velocity, directionality and relative track orientation of invasive cells were assessed in the presence or absence of inhibitors of phosphoinositide-3 kinase (PI3K) and/or beta-1 integrin.ResultsWe observed that assorted breast epithelial cells reacted differently to two-dimensional vs. staged, control (early) and tumor-associated (late), three-dimensional matrices. MCF-10A had a proliferative advantage on two-dimensional substrates while MCF-7 and MDA-MB-231 showed no difference. MCF-10A and MCF-7 formed morphologically distinguishable aggregates within three-dimensional matrices, while MDA-MB-231 exhibited increased spindle-shape morphologies and directional movements within three-dimensional matrices. Furthermore, MDA-MB-231 acquired a pattern of parallel oriented organization within tumor-associated, but not control matrices. Moreover, tumor-associated matrices induced PI3K and beta1-integrin dependent Akt/PKB activity in MDA-MB-231 cells. Interestingly, beta1-integrin (but not PI3K) regulated tumor-associated matrix-induced mesenchymal invasion which, when inhibited, resulted in a change of invasive strategy rather than impeding invasion altogether.ConclusionWe propose that both cells and matrices are important to promote effective breast cancer cell invasion through three-dimensional matrices and that beta1-integrin inhibition is not necessarily sufficient to block tumor-matrix induced breast cancer cell invasion. Additionally, we believe that characterizing stroma staging (e.g., early vs. late or tumor-associated) might be beneficial for predicting matrix-induced cancer cell responses in order to facilitate the selection of therapies.
Highlights
Interactions between cancer cells and stroma are critical for growth and invasiveness of epithelial tumors
Staged fibroblast-derived 3D extracellular matrix (ECM) do not impart a preferential growth environment to normal or tumorigenic breast epithelial cells To test whether our stromal staged mesenchymal ECMs induce breast epithelial cell growth, we cultured MCF10A, MCF-7 or MDA-MB-231 cells in 2D conditions, control or tumor-associated 3D ECMs and quantitatively measured their growth rates during a period of 3 days
These results suggested that fibroblast-derived 3D ECMs differentially regulate the growth rates of some, but not all, epithelial cells
Summary
Interactions between cancer cells and stroma are critical for growth and invasiveness of epithelial tumors. Changes in the stroma include appearance of discontinuities in the basement membrane surrounding the growing tumor, immune responses, formation of new vessels, and a desmoplastic reaction that includes activated fibroblasts (myofibroblasts) and remodeling of their mesenchymal extracellular matrix (ECM) [11,12,13,14,15] Both direct and indirect interactions between cancer cells and the mesenchyme are responsible for triggering the activation of the tumor-associated stroma (e.g., desmoplasia), creating a permissive environment in support of tumor development and cell invasion [5,13,16]. It has been proposed that tumor cells can transition between these invasive strategies in response to tumor-induced stromal plasticity [26,27]
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