title: Soluble endoglin antagonizes Met signaling in spindle carcinoma cells.
abstract: Increased levels of soluble endoglin (Sol-Eng) correlate with poor outcome in human cancer. We have previously shown that shedding of membrane endoglin, and concomitant release of Sol-Eng is a late event in chemical mouse skin carcinogenesis associated with the development of undifferentiated spindle cell carcinomas (SpCCs). In this report, we show that mouse skin SpCCs exhibit a high expression of hepatocyte growth factor (HGF) and an elevated ratio of its active tyrosine kinase receptor Met versus total Met levels. We have evaluated the effect of Sol-Eng in spindle carcinoma cells by transfection of a cDNA encoding most of the endoglin ectodomain or by using purified recombinant Sol-Eng. We found that Sol-Eng inhibited both mitogen-activated protein kinase (MAPK) activity and cell growth in vitro and in vivo. Sol-Eng also blocked MAPK activation by transforming growth factor-β1 (TGF-β1) and impaired both basal and HGF-induced activation of Met and downstream MAPK. Moreover, Sol-Eng strongly reduced basal and HGF-stimulated spindle cell migration and invasion. Both Sol-Eng and full-length endoglin were shown to interact with Met by coimmunoprecipitation experiments. However, full-length endoglin expressed at the plasma membrane of spindle carcinoma cells had no effect on Met signaling activity, and was unable to inhibit HGF-induced cell migration/invasion. These results point to a paradoxical suppressor role for Sol-Eng in carcinogenesis.
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain and Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Gaelle
authors.initials: G
authors.lastname: del Castillo
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain and Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Sánchez-Blanco
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain and Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Martín-Villar
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Valbuena-Diez
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Langa
authors.affiliation: Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pérez-Gómez
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain and Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Renart
authors.affiliation: Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Bernabéu
authors.affiliation: Instituto de Investigaciones Biomédicas Alberto Sols, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain and Centro de Investigaciones Biológicas, CSIC, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain Present address: Departamento de Bioquímica y Biología Molecular, Facultad de Biología, Universidad Complutense, 28040 Madrid, Spain. mquintanilla@iib.uam.es.
authors.forename: Miguel
authors.initials: M
authors.lastname: Quintanilla
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D000071063:Endoglin; D004789:Enzyme Activation; D005260:Female; D057809:HEK293 Cells; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011379:Prognosis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012509:Sarcoma / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D015703:Antigens, CD; D018076:DNA, Complementary; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D053773:Transforming Growth Factor beta1; D015127:9,10-Dimethyl-1,2-benzanthracene; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate