Expression of Nociceptive Ligands in Canine Osteosarcoma

Shor, S.; Fadl-Alla, Bahaa; Pondenis, Holly C.; Zhang, X.; Wycislo, Kathryn L.; Lezmi, Stéphane; Fan, Timothy M.

doi:10.1111/jvim.12511

Cited by 15 publications

(15 citation statements)

References 36 publications

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“…38 Specifically in OSA of dogs, PGE 2 is increased in both canine OSA cell lines and in naturally occurring tumors, 39 COX-2, microsomal PGE 2 synthase-1, and PGE 2 receptor are demonstrated to be increased in OSA lesions using immunohistochemistry staining, 40 and OSA cells from dogs secrete PGE 2 . 41 Our findings of increased PGE 2 in dogs with OSA are in accordance with these previous reports, and emphasize the ability of PGE 2 to induce immunopathology in OSA.…”

Section: Discussionsupporting

confidence: 93%

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

Tuohy

Lascelles

Griffith

et al. 2016

Veterinary Internal Medicne

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BackgroundMonocytes/macrophages are likely key cells in immune modulation in dogs with osteosarcoma (OSA). Increased peripheral monocyte counts are negatively correlated with shorter disease‐free intervals in dogs with OSA. Understanding the monocyte/macrophage's modulatory role in dogs with OSA can direct further studies in immunotherapy development for OSA.Hypothesis/ObjectivesThat OSA evades the immune response by down‐regulating monocyte chemokine receptor expression and migratory function, and suppresses host immune responses.AnimalsEighteen dogs with OSA that have not received definitive treatment and 14 healthy age‐matched controlsMethodsClinical study—expression of peripheral blood monocyte cell surface receptors, monocyte mRNA expression and cytokine secretion, monocyte chemotaxis, and survival were compared between clinical dogs with OSA and healthy control dogs.ResultsCell surface expression of multiple chemokine receptors is significantly down‐regulated in peripheral blood monocytes of dogs with OSA. The percentage expression of CCR2 (median 58%, range 2–94%) and CXCR2 expression (median 54%, range 2–92%) was higher in control dogs compared to dogs with OSA (CCR2 median 29%, range 3–45%, P = 0.0006; CXCR2 median 23%, range 0.2–52%, P = 0.0007). Prostaglandin E2 (PGE 2) (OSA, median 347.36 pg/mL, range 103.4–1268.5; control, 136.23 pg/mL, range 69.93–542.6, P = .04) and tumor necrosis factor‐alpha (TNF‐α) (P = .02) levels are increased in OSA monocyte culture supernatants compared to controls. Peripheral blood monocytes of dogs with OSA exhibit decreased chemotactic function when compared to control dogs (OSA, median 1.2 directed to random migration, range 0.8–1.25; control, 1.6, range of 0.9–1.8, P = .018).Conclusions and Clinical ImportanceDogs with OSA have decreased monocyte chemokine receptor expression and monocyte chemotaxis, potential mechanisms by which OSA might evade the immune response. Reversal of monocyte dysfunction using immunotherapy could improve survival in dogs with OSA.

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Section: Discussionsupporting

confidence: 93%

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

Tuohy

Lascelles

Griffith

et al. 2016

Veterinary Internal Medicne

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“…Our findings complement and extend existing knowledge regarding ET A R signaling in OS, and in particular the relevance of ET‐1 in the biology of canine OS . As indicated by the protein expression studies, canine OS cell lines and spontaneous tumor samples co‐express both receptor and cognate ligand, findings that substantiate the potential existence of a paracrine or autocrine signaling pathway that could be subverted by malignant osteoblasts.…”

Section: Discussionsupporting

confidence: 81%

The Association of Endothelin‐1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma

Neumann

Pondenis

Masyr

et al. 2015

Veterinary Internal Medicne

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BackgroundCanine 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.HypothesisThe 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.Animals45 dogs with appendicular OS.MethodsThe 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.ResultsCanine 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 ImportanceCanine 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.

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“…For example, primary afferent sensory neurons from the bone are restricted to specific A-delta and C-fibers [46]. In addition, recent research identified that canine OSA cells express and secrete nerve growth factor, endothelin-1 and prostaglandin E 2 which potentially participate in malignant bone pain [9]. Finally, microfracture can result from progressive osteolysis by activated osteoclasts [7].…”

Section: Discussionmentioning

confidence: 99%

“…These clinical signs tend to progress over time and patients become severely affected with altered function and QoL [7,8]. The actual incidence and characteristics of cancer pain in dogs remain unknown [9]. Nevertheless, given that dogs frequently present with advanced-stage cancer at initial evaluation and have similar cancer biology when compared with humans [10], it is reasonable to presume that canine patients experience a similar pain profile [2].…”

Section: Introductionmentioning

confidence: 99%

Pain characterization and response to palliative care in dogs with naturally-occurring appendicular osteosarcoma: An open label clinical trial

et al. 2018

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This study aimed to characterize bone cancer pain (quantitative sensory testing (QST), stance asymmetry index, actimetry, scores of pain and quality of life (QoL)) in dogs with appendicular osteosarcoma (OSA), and to evaluate a stepwise palliative analgesic treatment.The pain profile of thirteen client-owned dogs with OSA was compared with seven healthy dogs. Dogs with OSA were then enrolled in a prospective, open-label, clinical trial. Outcome measures included: primary and secondary mechanical thresholds (MT), conditioned pain modulation (CPM), stance asymmetry index, actimetry (most and least active periods), visual analog scales and QoL. After baseline assessments, stepwise treatment comprised orally administered cimicoxib (2 mg/kg q 24h), amitriptyline (1–1.5 mg/kg q 24h) and gabapentin (10 mg/kg q 8h); re-evaluations were performed after 14 (D14), 21 (D21) and 28 (D28) days, respectively. Statistics used mixed linear models (α = 5%; one-sided). Centralized nociceptive sensitivity (primary and secondary MT, and dynamic allodynia) was recorded in OSA dogs. Healthy dogs had responsive CPM, but CPM was deficient in OSA dogs. Construct validity was observed for the QST protocol. Asymmetry index was significantly present in OSA dogs. The CPM improved significantly at D14. When compared with baseline (log mean ± SD: 4.1 ± 0.04), most active actimetry significantly improved at D14 (4.3 ± 0.04), D21 and D28 (4.2 ± 0.04 for both). When compared with baseline, least active actimetry significantly decreased after treatment at all time-points indicating improvement in night-time restlessness. No other significant treatment effect was observed. Except for tactile threshold and actimetry, all outcomes worsened when gabapentin was added to cimicoxib-amitriptyline. Dogs with bone cancer are affected by widespread somatosensory sensitivity characterized by peripheral and central sensitization and have a deficient inhibitory system. This severe pain is mostly refractory to palliative analgesic treatment, and the latter was only detected by specific and sensitive outcomes.

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Expression of Nociceptive Ligands in Canine Osteosarcoma

Cited by 15 publications

References 36 publications

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

Association of Canine Osteosarcoma and Monocyte Phenotype and Chemotactic Function

The Association of Endothelin‐1 Signaling with Bone Alkaline Phosphatase Expression and Protumorigenic Activities in Canine Osteosarcoma

Pain characterization and response to palliative care in dogs with naturally-occurring appendicular osteosarcoma: An open label clinical trial

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