Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration

作者：Irene Acerbi, Luke Cassereau, Ivory S. Dean, Quanming Shi, Alfred Au, Chanhyuk Park, Y. Y. Chen, Jan Liphardt, E. Shelley Hwang, Valerie Marie Weaver · 发表于：Integrative Biology · 年份：2015 · DOI：10.1039/c5ib00040h · 被引用次数：1104 · 研究领域：Cancer Cells and Metastasis、3D Printing in Biomedical Research、Monoclonal and Polyclonal Antibodies Research

Tumors are stiff and data suggest that the extracellular matrix stiffening that correlates with experimental mammary malignancy drives tumor invasion and metastasis. Nevertheless, the relationship between tissue and extracellular matrix stiffness and human breast cancer progression and aggression remains unclear. We undertook a biophysical and biochemical assessment of stromal-epithelial interactions in noninvasive, invasive and normal adjacent human breast tissue and in breast cancers of increasingly aggressive subtype. Our analysis revealed that human breast cancer transformation is accompanied by an incremental increase in collagen deposition and a progressive linearization and thickening of interstitial collagen. The linearization of collagen was visualized as an overall increase in tissue birefringence and was most striking at the invasive front of the tumor where the stiffness of the stroma and cellular mechanosignaling were the highest. Amongst breast cancer subtypes we found that the stroma at the invasive region of the more aggressive Basal-like and Her2 tumor subtypes was the most heterogeneous and the stiffest when compared to the less aggressive luminal A and B subtypes. Intriguingly, we quantified the greatest number of infiltrating macrophages and the highest level of TGF beta signaling within the cells at the invasive front. We also established that stroma stiffness and the level of cellular TGF beta signaling positively correlated with each other and with the ...