Inhibition of invasion and metastasis by glypican-3 in a syngeneic breast cancer model.
Glypican-3 (GPC3), a proteoglycan bound to the cell membrane through a GPI anchor, is widely expressed in the embryo but down regulated in most adult tissues, with some exceptions as mammary cells. GPC3 is involved in the regulation of cell proliferation and survival in specific cell types. LM3, a murine mammary tumor cell line unable to express GPC3, was stably transfected with the rat GPC3 gene to analyze its role in tumor progression. Upon injection into syngeneic BALB/c mice LM3-GPC3 clones showed less local invasiveness and developed fewer spontaneous and experimental lung metastasis than controls. GPC3-expressing cells were more sensitive to apoptosis induced by serum depletion, exhibited a delay in the first steps of spreading and were less motile than controls. On the other hand, LM3-GPC3 cells were significantly more adherent to FN than control ones. We observed that GPC3 transfectants presented a higher expression of E-cadherin and beta-catenin, molecules whose down regulation has been associated with tumor progression. Exogenous TGF-beta increased MMP-9 activity in both control and GPC3-expressing cells, but did not modulate MMP-2. Contrarily, GPC3 expression prevented the increase of MMP-2 activity induced by IGF-II. Our results suggest that GPC3 has a protective role against mammary cancer progression.
Peters
M G
MG
Research Area, Cell Biology Department, Institute of Oncology Angel H. Roffo, University of Buenos Aires, Buenos Aires, Argentina.
Farías
E
E
Colombo
L
L
Filmus
J
J
Puricelli
L
L
Bal de Kier Joffé
E
E
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism* / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D053673:Glypicans; D019812:Heparan Sulfate Proteoglycans; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II