title: Arresten, a collagen-derived angiogenesis inhibitor, suppresses invasion of squamous cell carcinoma.
abstract: The turnover of extracellular matrix liberates various cryptic molecules with novel biological activity. Among these are the collagen-derived anti-angiogenic fragments, some of which are suggested to affect carcinoma cells also directly. Arresten is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of the basement membrane collagen IV α1 chain. As the mere prevention of tumor angiogenesis leads to hypoxia that can result in selection of more aggressive cell types and reduces the efficacy of chemotherapy, we aimed here to elucidate how arresten influences the aggressive human carcinoma cells. Arresten efficiently inhibited migration and invasion of HSC-3 tongue carcinoma cells in culture and in an organotypic model. Subcutaneous Arr-HSC xenografts grew markedly more slowly in nude mice and showed reduced tumor cell proliferation, vessel density and local invasiveness. In the organotypic assay, HSC-3 cells overproducing arresten (Arr-HSC) showed induction of cell death. In monolayer culture the Arr-HSC cells grew in aggregated cobblestone-like clusters and, relative to the control cells, showed increased expression and localization of epithelial marker E-cadherin in cell-cell contacts. Application of electric cell-substrate impedance sensing (ECIS) further supported our observations on altered morphology and motility of the Arr-HSC cells. Administration of a function-blocking α1 integrin antibody abolished the impedance difference between the Arr-HSC and control cells suggesting that the effect of arresten on promotion of HSC-3 cell-cell contacts and cell spreading is at least partly mediated by α1β1 integrin. Collectively, our data suggest novel roles for arresten in the regulation of oral squamous carcinoma cell proliferation, survival, motility and invasion through the modulation of cell differentiation state and integrin signaling.
authors.affiliation: Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.forename: Ilkka
authors.initials: I
authors.lastname: Alahuhta
authors.forename: Sini
authors.initials: S
authors.lastname: Nurmenniemi
authors.forename: Juho
authors.initials: J
authors.lastname: Suojanen
authors.forename: Riitta
authors.initials: R
authors.lastname: Palovuori
authors.forename: Susanna
authors.initials: S
authors.lastname: Teppo
authors.forename: Timo
authors.initials: T
authors.lastname: Sorsa
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Tuula
authors.initials: T
authors.lastname: Salo
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.forename: Pia
authors.initials: P
authors.lastname: Nyberg
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003094:Collagen / Q000737:chemistry*; D024141:Collagen Type IV / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017097:Electric Impedance; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006801:Humans; D039222:Integrin alpha1beta1 / Q000276:immunology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014062:Tongue Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D019138:Antibodies, Blocking; C547475:COL4A1 protein, human; D015820:Cadherins; D024141:Collagen Type IV; D039222:Integrin alpha1beta1; D003094:Collagen