title: Soluble MMP-14 produced by bone marrow-derived stromal cells sheds epithelial endoglin modulating the migratory properties of human breast cancer cells.
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-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 biotin-neutravidin 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.
authors.affiliation: Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Tobar
authors.affiliation: Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain.
authors.forename: M Celeste
authors.initials: MC
authors.lastname: Avalos
authors.affiliation: Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain.
authors.forename: Nicolás
authors.initials: N
authors.lastname: Méndez
authors.affiliation: Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
authors.forename: Patricio C
authors.initials: PC
authors.lastname: Smith
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabeu
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintanilla
authors.affiliation: Laboratorio de Biología Celular, INTA, Universidad de Chile, Santiago 7830490, Chile, Laboratorio de Fisiología Periodontal, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain and Instituto de Investigaciones Biomédicas Alberto Sols, CSIC, 28029 Madrid, Spain jmartine@inta.uchile.cl.
authors.forename: Jorge
authors.initials: J
authors.lastname: Martínez
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D000071063:Endoglin; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D008856:Microscopy, Fluorescence; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D017077:Culture Media, Conditioned; C064206:ENG protein, human; D000071063:Endoglin; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14