Open AccessDownregulation of CXCR 4 Expression and Functionality After Zoledronate Exposure in Canine Osteosarcoma
Author(s) -
Byrum M.L.,
Pondenis H.C.,
Fredrickson R.L.,
Wycislo K.L.,
Fan T.M.
Publication year - 2016
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.14257
Subject(s) - downregulation and upregulation , chemokine receptor , cancer research , medicine , chemokine , signal transduction , osteosarcoma , cell culture , receptor , microbiology and biotechnology , biology , gene , biochemistry , genetics
Background The establishment and progression of metastases remains the life‐limiting factor for dogs diagnosed with osteosarcoma ( OS ). The pattern of metastases is likely regulated through interactions between chemokine receptors and chemokines, and perturbations in these signaling cascades responsible for cytoskeletal organization and directional migration have the potential to alter metastatic cell trafficking behaviors. Hypothesis Zoledronate will impair directional migration of OS cells through downregulation of chemokine (C‐X‐C motif) receptor 4 ( CXCR 4) expression and functionality. Samples Nineteen archived tumor specimens and plasma from 20 dogs with OS . Methods Prospectively, the expressions of CXCR 4 were studied in OS cell lines and spontaneous tumor samples. The effect of zoledronate on CXCR 4 expression and functionality was investigated by characterizing responses in 3 OS cell lines. In 19 OS specimens and 20 dogs with OS , changes in CXCR 4 expression and circulating CXCR 4 concentrations were characterized in response to zoledronate therapy respectively. Results All canine OS cells express CXCR 4, and zoledronate reduces CXCR 4 expression and functionality by 27.7% ( P < .0001), through augmented proteasome degradation and reduced prenylation of heterotrimeric G‐proteins in 33% of tumor cell lines evaluated. In OS ‐bearing dogs, zoledronate reduces CXCR 4 expressions by 40% within the primary tumor compared to untreated controls ( P = .03) and also decreases the circulating concentrations of CXCR 4 in 18 of 20 dogs with OS . Conclusions and clinical importance Zoledronate can alter CXCR 4 expression and functionality in OS cells, and consequent perturbations in CXCR 4 intracellular signaling cascades might influence patterns of metastases.