title: The NC11 domain of human collagen XVI induces vasculogenic mimicry in oral squamous cell carcinoma cells.
abstract: Collagen XVI, a fibril-associated collagen with interrupted triple helix (FACIT) collagen, is involved in oral squamous cell carcinoma (OSCC) and glioblastoma progression. The NC11 domain of collagen XVI has been described previously with a strong implication in physiological processes. We detected the non-collagenous (NC) 11-domain in supernatants of OSCC cells after recombinant expression of full-length collagen XVI and in sera from OSCC patients and healthy individuals. Stable expression of NC11-green fluorescent protein (GFP) fusion protein in OSCC cells initiated proliferation control and block of anchorage-independent growth. Moreover, the NC11 domain triggered the generation of tubular-like net structures on laminin-rich matrix in contrast to mock-GFP control cells and cells expressing full-length collagen XVI. Taqman® quantitative PCR and diaminobenzidine staining in 2D- and 3D cell culture revealed a significantly increased gene and protein expression of VEGFR1, VEGFR2 and uPAR in recombinant NC11-GFP-expressing cells. Specific VEGF receptor inhibition with Axitinib or fetal calf serum heat inactivation prevented formation of tubular-like net structures. Accordantly, NC11-GFP coated culture slides led to an increase of focal adhesion contact formation and the upregulation of VEGFR1 and uPAR in three different non-transfected OSCC cell lines. In summary, we suggest that the NC11 domain of collagen XVI is a potential biomarker for OSCC and triggers vasculogenic mimicry via upregulation of endothelial receptors VEGFR1, VEGFR2 and uPAR in 2D- and 3D OSCC cell culture conditions.
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg 93059, 93053 Regensburg, Germany, Centre for Medical Biotechnology, BioPark I 93053, Regensburg, Germany and.
authors.forename: Konstanze B
authors.initials: KB
authors.lastname: Bedal
authors.affiliation: Centre for Medical Biotechnology, BioPark I 93053, Regensburg, Germany and Department of Orthopaedic Surgery, Experimental Orthopaedics, University Hospital Regensburg 93059, Regensburg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Grässel
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg 93059, 93053 Regensburg, Germany.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Spanier
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg 93059, 93053 Regensburg, Germany.
authors.forename: Torsten E
authors.initials: TE
authors.lastname: Reichert
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Hospital Regensburg 93059, 93053 Regensburg, Germany, Centre for Medical Biotechnology, BioPark I 93053, Regensburg, Germany and Richard.Bauer@klinik.uni-regensburg.de.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bauer
mesh_terms: D000368:Aged; D042501:Angiogenic Proteins / Q000502:physiology; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000098:blood supply* / Q000235:genetics; D045744:Cell Line, Tumor; D003094:Collagen / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000097:blood / Q000098:blood supply* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000378:metabolism; D017434:Protein Structure, Tertiary; D015854:Up-Regulation; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D042501:Angiogenic Proteins; C481130:COL16A1 protein, human; D003094:Collagen; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2