title: Invasion of tumorigenic HT1080 cells is impeded by blocking or downregulating the 37-kDa/67-kDa laminin receptor.
abstract: The 37-kDa/67-kDa laminin receptor precursor/laminin receptor (LRP/LR) acting as a receptor for prions and viruses is overexpressed in various cancer cell lines, and their metastatic potential correlates with LRP/LR levels. We analyzed the tumorigenic fibrosarcoma cell line HT1080 regarding 37-kDa/67-kDa LRP/LR levels and its invasive potential. Compared to the less invasive embryonic fibroblast cell line NIH3T3, the tumorigenic HT1080 cells display approximately 1.6-fold higher cell-surface levels of LRP/LR. We show that anti-LRP/LR tools interfere with the invasive potential of HT1080 cells. Anti-LRP/LR single-chain variable fragment antibody (scFv) iS18 generated by chain shuffling from parental scFv S18 and its full-length version immunoglobulin G1-iS18 reduced the invasive potential of HT1080 cells significantly by 37% and 38%, respectively. HT1080 cells transfected with lentiviral plasmids expressing small interfering RNAs directed against LRP mRNA showed reduced LRP levels by approximately 44%, concomitant with a significant decrease in the invasive potential by approximately 37%. The polysulfated glycans HM2602 and pentosan polysulfate (SP-54), both capable of blocking LRP/LR, reduced the invasive potential by 20% and 35%, respectively. Adhesion of HT1080 cells to laminin-1 was significantly impeded by scFv iS18 and immunoglobulin G1-iS18 by 60% and 68%, respectively, and by SP-54 and HM2602 by 80%, suggesting that the reduced invasive capacity achieved by these tools is due to the perturbation of the LRP/LR-laminin interaction on the cell surface. Our in vitro data suggest that reagents directed against LRP/LR or LRP mRNA such as antibodies, polysulfated glycans, or small interfering RNAs, previously shown to encompass an anti-prion activity by blocking or downregulating the prion receptor LRP/LR, might also be potential cancer therapeutics blocking metastasis by interfering with the LRP/LR-laminin interaction in neoplastic tissues.
authors.affiliation: Laboratorium für Molekulare Biologie-Genzentrum-Institut für Biochemie der LMU München, Feodor-Lynen-Str. 25, D-81377 München, Germany.
authors.forename: Chantal
authors.initials: C
authors.lastname: Zuber
authors.forename: Stefan
authors.initials: S
authors.lastname: Knackmuss
authors.forename: Georgeta
authors.initials: G
authors.lastname: Zemora
authors.forename: Uwe
authors.initials: U
authors.lastname: Reusch
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Vlasova
authors.forename: Daniela
authors.initials: D
authors.lastname: Diehl
authors.forename: Vera
authors.initials: V
authors.lastname: Mick
authors.forename: Karin
authors.initials: K
authors.lastname: Hoffmann
authors.forename: Daphne
authors.initials: D
authors.lastname: Nikles
authors.forename: Thomas
authors.initials: T
authors.lastname: Fröhlich
authors.forename: Georg J
authors.initials: GJ
authors.lastname: Arnold
authors.forename: Bertram
authors.initials: B
authors.lastname: Brenig
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Harald
authors.initials: H
authors.lastname: Lahm
authors.forename: Melvyn
authors.initials: M
authors.lastname: Little
authors.forename: Stefan
authors.initials: S
authors.lastname: Weiss
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D015536:Down-Regulation; D006801:Humans; D007797:Laminin / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D010957:Plasmids / Q000378:metabolism; D018620:PrPSc Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017474:Receptors, Laminin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D007797:Laminin; D018620:PrPSc Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017474:Receptors, Laminin; C121346:laminin 1