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Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells

AuthorsTobar, Nicolás; Avalos, M. Celeste; Méndez, Nicolás; Smith, Patricio C.; Bernabéu, Carmelo ; Quintanilla, Miguel ; Martínez, Jorge
Issue Date2014
PublisherOxford University Press
CitationCarcinogenesis 35(8): 1770-1779 (2014)
AbstractIt has been proposed that epithelial cells can acquire invasive properties through exposure to paracrine signals originated from mesenchymal cells within the tumor microenvironment. Transforming growth factor-β (TGF-β) has been revealed as an active factor that mediates the epithelial-stroma cross-talk that facilitates cell invasion and metastasis. TGF-β signaling is modulated by the coreceptor Endoglin (Eng), which shows a tumor suppressor activity in epithelial cells and regulates the ALK1- Smad1,5,8 as well as the ALK5-Smad2,3 signaling pathways. In the current work, we present evidence showing that cell surface Eng abundance in epithelial MCF-7 breast cancer cells is inversely related with cell motility. Shedding of Eng in MCF-7 cell surface by soluble matrix metalloproteinase-14 (MMP-14) derived from the HS-5 bone-marrow-derived cell line induces a motile epithelial phenotype. On the other hand, restoration of full-length Eng expression blocks the stromal stimulus on migration. Processing of surface Eng by stromal factors was demonstrated by biotinneutravidin labeling of cell surface proteins and this processing generated a shift in TGF-β signaling through the activation of Smad2,3 pathway. Stromal MMP-14 abundance was stimulated by TGF-β secreted by MCF-7 cells acting in a paracrine manner. In turn, the stromal proteolytic activity of soluble MMP-14, by inducing Eng shedding, promoted malignant progression. From these data, and due to the capacity of TGF-β to regulate malignancy in epithelial cancer, we propose that stromal-dependent epithelial Eng shedding constitutes a putative mechanism that exerts an environmental control of cell malignancy.
Publisher version (URL)https://doi.org/10.1093/carcin/bgu061
Identifiersdoi: 10.1093/carcin/bgu061
issn: 0143-3334
e-issn: 1460-2180
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