Open AccessThe Association of Endothelin‐1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma
Author(s) -
Neumann Z.L.,
Pondenis H.C.,
Masyr A.,
Byrum M.L.,
Wycislo K.L.,
Fan T.M.
Publication year - 2015
Publication title -
journal of veterinary internal medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.356
H-Index - 103
eISSN - 1939-1676
pISSN - 0891-6640
DOI - 10.1111/jvim.13635
Subject(s) - alkaline phosphatase , endothelin receptor , osteosarcoma , endocrinology , osteoblast , medicine , endothelin 1 , signal transduction , bone resorption , cancer research , receptor , chemistry , biology , microbiology and biotechnology , biochemistry , enzyme , in vitro
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. Hypothesis 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. Animals 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 and Clinical Importance 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.