title: Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model.
abstract: The extracellular matrix molecule tenascin-C (TNC) is a major component of the cancer-specific matrix, and high TNC expression is linked to poor prognosis in several cancers. To provide a comprehensive understanding of TNC's functions in cancer, we established an immune-competent transgenic mouse model of pancreatic β-cell carcinogenesis with varying levels of TNC expression and compared stochastic neuroendocrine tumor formation in abundance or absence of TNC. We show that TNC promotes tumor cell survival, the angiogenic switch, more and leaky vessels, carcinoma progression, and lung micrometastasis. TNC downregulates Dickkopf-1 (DKK1) promoter activity through the blocking of actin stress fiber formation, activates Wnt signaling, and induces Wnt target genes in tumor and endothelial cells. Our results implicate DKK1 downregulation as an important mechanism underlying TNC-enhanced tumor progression through the provision of a proangiogenic tumor microenvironment.
authors.affiliation: Inserm U1109, MN3T Team, The Microenvironmental Niche in Tumorigenesis and Targeted Therapy, 3 Avenue Molière, 67200 Strasbourg, France; Université de Strasbourg, 67000 Strasbourg, France; LabEx Medalis, Université de Strasbourg, 67000 Strasbourg, France; Fédération de Médecine Translationnelle de Strasbourg (FMTS), 67000 Strasbourg, France.
authors.forename: Falk
authors.initials: F
authors.lastname: Saupe
authors.forename: Anja
authors.initials: A
authors.lastname: Schwenzer
authors.forename: Yundan
authors.initials: Y
authors.lastname: Jia
authors.forename: Isabelle
authors.initials: I
authors.lastname: Gasser
authors.forename: Caroline
authors.initials: C
authors.lastname: Spenlé
authors.forename: Benoit
authors.initials: B
authors.lastname: Langlois
authors.forename: Martial
authors.initials: M
authors.lastname: Kammerer
authors.forename: Olivier
authors.initials: O
authors.lastname: Lefebvre
authors.forename: Ruslan
authors.initials: R
authors.lastname: Hlushchuk
authors.forename: Tristan
authors.initials: T
authors.lastname: Rupp
authors.forename: Marija
authors.initials: M
authors.lastname: Marko
authors.forename: Michael
authors.initials: M
authors.lastname: van der Heyden
authors.forename: Gérard
authors.initials: G
authors.lastname: Cremel
authors.forename: Christiane
authors.initials: C
authors.lastname: Arnold
authors.forename: Annick
authors.initials: A
authors.lastname: Klein
authors.forename: Patricia
authors.initials: P
authors.lastname: Simon-Assmann
authors.forename: Valentin
authors.initials: V
authors.lastname: Djonov
authors.forename: Agnès
authors.initials: A
authors.lastname: Neuville-Méchine
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Julia
authors.initials: J
authors.lastname: Slotta-Huspenina
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.forename: Olivier
authors.initials: O
authors.lastname: de Wever
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
authors.forename: Thomas
authors.initials: T
authors.lastname: Hussenet
authors.forename: Gertraud
authors.initials: G
authors.lastname: Orend
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004195:Disease Models, Animal; D015536:Down-Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D019063:Tenascin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D019063:Tenascin; D051153:Wnt Proteins