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

Tobar N., M. Avalos MC, Méndez N, Smith PC. Bernabeu C, Quintanilla M. and Martínez J

Keywords: endoglin, shedding, MMP-14: cell migration

Abstract

It 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-beta (TGF-beta) has been revealed as an active factor that mediates the epithelial-stroma cross-talk that facilitates cell invasion and metastasis. TGF-beta 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 biotin-neutravidin labeling of cell surface proteins and this processing generated a shift in TGF-beta signaling through the activation of Smad2,3 pathway. Stromal MMP-14 abundance was stimulated by TGF-beta 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-beta 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.

Más información

Título según WOS: Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells
Título según SCOPUS: Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells
Título de la Revista: Carcinogenesis
Volumen: 35
Número: 8
Editorial: Oxford Academic
Fecha de publicación: 2014
Idioma: English
Financiamiento/Sponsor: FONDECYT 1120187
DOI:

10.1093/carcin/bgu061

Notas: ISI, SCOPUS - ISI, SCOPUS