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Investigating TrkA expression in canine appendicular osteosarcoma
T M Fan1, A M Barger, I T Sprandel
1Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802-4714, USA. t-fan@uiuc.edu
Background:
The tropomyosin-related kinase A (TrkA) proto-oncogene encodes for a receptor that binds with high affinity to the neurotrophin ligand, nerve growth factor (NGF). Intracellular signaling mediated by the TrkA/NGF axis orchestrates neuronal cell differentiation, mitogenesis, and survival. Interestingly, TrkA also is expressed by bone forming cells, and its signaling promotes antiapoptotic effects in actively dividing osteoblasts.
Hypothesis:
In canine immortalized cell lines and naturally occurring tumor samples, osteosarcoma (OSA) cells will express TrkA. In canine OSA cell lines, TrkA signaling will promote cell mitogenesis and survival.
Methods:
In vitro, TrkA expression in canine OSA cell lines was assessed by reverse transcriptase-polymerase chain reaction, flow cytometry, and immunocytochemistry. In vitro, the involvement of TrkA-mediated signaling for cell mitogenesis and survival were investigated with commercially available assays. In vivo, TrkA expression was evaluated in primary tumors and pulmonary metastases with immunocytochemistry and immunohistochemistry, respectively.
Results:
In vitro, canine OSA cells expressed TrkA mRNA and protein. Ligation of TrkA with exogenous NGF did not induce mitogenesis. Blockade of TrkA signaling with either a protein kinase inhibitor or NGF-neutralizing antibody induced apoptosis of canine OSA cell lines. In vivo, the majority (10/15) of canine OSA primary tumors and pulmonary metastases (9/12) expressed TrkA protein.
Conclusions And Clinical Importance:
Canine OSA cells express TrkA, and its signaling protects against apoptosis. Most dogs with spontaneously arising OSA express TrkA within their primary tumors and pulmonary metastatic lesions, warranting further investigations with TrkA antagonists as a novel treatment option for canine OSA.
Insights
Canine osteosarcoma cells express TrkA, a receptor tyrosine kinase. Blocking TrkA signaling induces apoptosis, suggesting TrkA antagonists may treat canine osteosarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- The tropomyosin-related kinase A (TrkA) receptor tyrosine kinase binds nerve growth factor (NGF).
- TrkA signaling is crucial for neuronal development and survival.
- TrkA is also expressed in osteoblasts, where it promotes survival.
Purpose of the Study:
- To determine if canine osteosarcoma (OSA) cells express TrkA.
- To investigate the role of TrkA signaling in canine OSA cell mitogenesis and survival.
Main Methods:
- TrkA expression was assessed in canine OSA cell lines and tumor samples using RT-PCR, flow cytometry, and immunohistochemistry.
- In vitro assays evaluated the impact of TrkA signaling on cell proliferation and survival.
- In vivo analysis examined TrkA expression in primary tumors and metastases.
Main Results:
- Canine OSA cells express TrkA mRNA and protein.
- Blocking TrkA signaling induced apoptosis in canine OSA cell lines.
- TrkA protein was detected in most primary canine OSA tumors and metastatic lesions.
Conclusions:
- Canine osteosarcoma cells express TrkA, and its signaling pathway confers protection against apoptosis.
- The presence of TrkA in canine OSA tumors and metastases suggests TrkA antagonists as a potential therapeutic strategy.
