title: Endostatin induces proliferation of oral carcinoma cells but its effect on invasion is modified by the tumor microenvironment.
abstract: The turnover of extracellular matrix liberates various cryptic molecules with novel biological activities. Endostatin is an endogenous angiogenesis inhibitor that is derived from the non-collagenous domain of collagen XVIII. Although there are a large number of studies on its anti-tumor effects, the molecular mechanisms are not yet completely understood, and the reasons why endostatin has not been successful in clinical trials are unclear. Research has mostly focused on its anti-angiogenic effect in tumors. Here, we aimed to elucidate how endostatin affects the behavior of aggressive tongue HSC-3 carcinoma cells that were transfected to overproduce endostatin. Endostatin inhibited the invasion of HSC-3 cells in a 3D collagen-fibroblast model. However, it had no effect on invasion in a human myoma organotypic model, which lacks vital fibroblasts. Recombinant endostatin was able to reduce the Transwell migration of normal fibroblasts, but had no effect on carcinoma associated fibroblasts. Surprisingly, endostatin increased the proliferation and decreased the apoptosis of cancer cells in organotypic models. Also subcutaneous tumors overproducing endostatin grew bigger, but showed less local invasion in nude mice xenografts. We conclude that endostatin affects directly to HSC-3 cells increasing their proliferation, but its net effect on cancer invasion seem to depend on the cellular composition and interactions of tumor microenvironment.
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Alahuhta
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Oulu Center for Cell-Matrix Research, University of Oulu, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Aikio
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Väyrynen
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Nurmenniemi
authors.affiliation: Department of Oral and Maxillo-facial Diseases, University of Helsinki, Helsinki University Central Hospital, Finland.
authors.forename: Juho
authors.initials: J
authors.lastname: Suojanen
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland.
authors.forename: Susanna
authors.initials: S
authors.lastname: Teppo
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Oulu Center for Cell-Matrix Research, University of Oulu, Finland.
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.affiliation: Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine, University of Oulu, Finland; Oulu Center for Cell-Matrix Research, University of Oulu, Finland.
authors.forename: Ritva
authors.initials: R
authors.lastname: Heljasvaara
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland; Department of Oral and Maxillo-facial Diseases, University of Helsinki, Helsinki University Central Hospital, Finland; Department of Oral Diagnosis, School of Dentistry, State University of Campinas, Piracicaba, Sao Paolo, Brazil.
authors.forename: Tuula
authors.initials: T
authors.lastname: Salo
authors.affiliation: Research Group of Cancer and Translational Medicine, Faculty of Medicine, University of Oulu, Finland; Medical Research Center, Oulu University Hospital, Oulu, Finland. Electronic address: pia.nyberg@oulu.fi.
authors.forename: Pia
authors.initials: P
authors.lastname: Nyberg
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D043169:Endostatins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009214:Myoma / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D014062:Tongue Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects*; D014594:Uterine Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D043169:Endostatins
keywords: Endostatin; Extracellular matrix; Organotypic models; Tongue carcinoma; Tumor invasion