Breast Fibroblasts Modulate Early Dissemination, Tumorigenesis, and Metastasis through Alteration of Extracellular Matrix Characteristics

Abstract

A wealth of evidence has now demonstrated that the microenvironment in which a tumorigenic cell evolves is as critical to its evolution as the genetic mutations it accrues. However, there is still relatively little known about how signals from the microenvironment contribute to the early events in the progression to malignancy. To address this question, we used a premalignant mammary model to examine how fibroblasts, and the extracellular matrix (ECM) proteins they secrete, influence progression to malignancy. Their effect on metastatic malignant cells was also assessed for comparison. We found that carcinoma-associated fibroblasts, and the distinct aligned ECM they deposit, can cause both premalignant and malignant mammary epithelial cells to assume a mesenchymal morphology that is associated with increased dissemination and metastasis, while benign reduction mammoplasty fibroblasts favor the maintenance of an epithelial morphology and constrain early dissemination, tumor growth, and metastasis. Our results suggest that normalizing the organization of the ECM could be effective in limiting systemic dissemination and tumor growth.

Carcinoma-associated fibroblasts: orchestrating the composition of malignancy

“…This is in stark contrast to the historical view in which the scientific and patient communities have focused their attention on epithelial cancer cells, since the vast majority of human cancers exhibits epithelial abnormalities, and mutational changes in these cells are readily observable. However, the last 15 years have seen a shift in this momentum, driven, to a large extent, by a flourishing literature that has built a strong case for a major involvement of the stroma in restraining (Bissell and Hines 2011;Dumont et al 2013) or facilitating cancer progression (Olumi et al 1999; Kalluri and Zeisberg 2006;Tlsty and Coussens 2006;Finak et al 2008;Dumont et al 2013). Recent provocative reports have further extended this novel concept by unequivocally demonstrating that, in some cancers, the stroma goes beyond playing the role of a facilitator of the tumorigenic process.…”

“…Indeed, interactions of CAFs with cellular components of the immune system contribute, to a large extent, to the tumor-promoting role of CAFs through immunosuppression and sustained inflammation (Liao et al 2009;Erez et al 2010;Quante et al 2011;Servais and Erez 2013). Moreover, the CAF status has an impact on the clinical behavior of a tumor (Chang et al 2004(Chang et al , 2005Kalluri and Zeisberg 2006;Tlsty and Coussens 2006;Finak et al 2008;Berdiel-Acer et al 2014), in particular early and targeted metastasis (Dumont et al 2013;Zhang et al 2013;Calon et al 2014).…”

Updated Landscape of the Tumor Microenvironment and Targeting Strategies in an Era of Precision Medicine

“…CAFs accumulated in the TME are subject to activation by cytokines and growth factors present in the nearby niches, such as fibroblast growth factor (FGF), monocyte chemotactic protein 1 (MCP1), PDGF, TGF-β and secreted proteases [8,9]. Once activated, CAFs release proinflammatory factors to activate the nuclear factor (NF)-KB signaling in transformed cells, a typical cell-cell cross talk that significantly promotes tumorigenesis [10].…”

Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

“…6 Tumors can recruit TME-supporting cells by modifying the normal tissue environment, e.g., cancer-associated fibroblasts, which are involved in carcinogenesis stimulation, 7,8 and tumor-associated macrophages, which become altered during cancer development. 9 Therefore, TME must be considered a dynamic entity remodeling with the tumor itself.…”