Endoglin expression in metastatic breast cancer cells enhances their invasive phenotype.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
Oxmann
D
D
Department of Anatomy, University of Kiel, Kiel, Germany.
Held-Feindt
J
J
Stark
A M
AM
Hattermann
K
K
Yoneda
T
T
Mentlein
R
R
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002465:Cell Movement; D000071063:Endoglin; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D011956:Receptors, Cell Surface; D016212:Transforming Growth Factor beta; D053505:Matrix Metalloproteinases, Secreted; C108362:matrix metalloproteinase 19; D020781:Matrix Metalloproteinase 1