title: The Association of Endothelin-1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma.
abstract: BACKGROUND
  Canine osteosarcoma (OS) is an aggressive sarcoma characterized by pathologic skeletal resorption and pulmonary metastases. A number of negative prognostic factors, including bone alkaline phosphatase, have been identified in dogs with OS, but the underlying biologic factors responsible for such observations have not been thoroughly investigated. Endothelin-1-mediated signaling is active during bone repair, and is responsible for osteoblast migration, survival, proliferation, and bone alkaline phosphatase expression.
  
  
  OBJECTIVE
  The endothelin-1 signaling axis is active in canine OS cells, and this pathway is utilized by malignant osteoblasts for promoting cellular migration, survival, proliferation, and bone alkaline phosphatase activities.
  
  
  METHODS
  45 dogs with appendicular OS.
  
  
  METHODS
  The expressions of endothelin-1 and endothelin A receptor were studied in OS cell lines and in samples from spontaneously occurring tumors. Activities mediated by endothelin-1 signaling were investigated by characterizing responses in 3 OS cell lines. In 45 dogs with OS, bone alkaline phosphatase concentrations were correlated with primary tumor osteoproductivity.
  
  
  RESULTS
  Canine OS cells express endothelin-1 and endothelin A receptor, and this signaling axis mediates OS migration, survival, proliferation, and bone alkaline phosphatase activities. In OS-bearing dogs, circulating bone alkaline phosphatase activities were positively correlated with primary tumor relative bone mineral densities.
  
  
  CONCLUSIONS
  Canine OS cells express endothelin-1 and functional endothelin A receptors, with the potential for a protumorigenic signaling loop. Increases in bone alkaline phosphatase activity are associated with osteoblastic OS lesions, and might be an epiphenomenon of active endothelin-1 signaling or excessive osteoproduction within the localized bone microenvironment.
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
authors.forename: Z L
authors.initials: ZL
authors.lastname: Neumann
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
authors.forename: H C
authors.initials: HC
authors.lastname: Pondenis
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
authors.forename: A
authors.initials: A
authors.lastname: Masyr
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
authors.forename: M L
authors.initials: ML
authors.lastname: Byrum
authors.affiliation: Department of Pathobiology, University of Illinois, Urbana, IL.
authors.forename: K L
authors.initials: KL
authors.lastname: Wycislo
authors.affiliation: Department of Veterinary Clinical Medicine, University of Illinois, Urbana, IL.
authors.forename: T M
authors.initials: TM
authors.lastname: Fan
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015519:Bone Density; D001859:Bone Neoplasms / Q000378:metabolism / Q000662:veterinary; D045744:Cell Line, Tumor; D054443:Cell Migration Assays; D004283:Dog Diseases / Q000378:metabolism*; D004285:Dogs; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D012516:Osteosarcoma / Q000378:metabolism / Q000662:veterinary*; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D019332:Endothelin-1; D044022:Receptor, Endothelin A; D000469:Alkaline Phosphatase
keywords: Cell migration and survival; Osteoblastic response; Prognostic factor