Characterization, expression and function of c-Met in canine spontaneous cancers
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Published on: February 28, 2014
A T Liao1, M McMahon, C London
1Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Abstract:
Aberrant expression of the proto-oncogene c-Met has been noted in a variety of human cancers. To better define the potential role of Met dysregulation in canine cancer, the canine Met, hepatocyte growth factor (HGF) and HGF activator were cloned. Inappropriate expression of Met was present in canine tumour cell lines derived from a wide variety of cancers. Furthermore, both HGF and HGF activator were also expressed in several of these cell lines, providing evidence of a possible autocrine loop of Met activation. Stimulation of tumour cell lines with recombinant human HGF induced Met autophosphorylation, as well as activation of the downstream signalling elements Gab-1, Akt and Erk1/2. Scattering of tumour cells and migration across a defect occurred in response to HGF stimulation. The Met inhibitor PHA665752 blocked both HGF-induced phosphorylation of canine Met and HGF-mediated cell cycling, scattering and migration. These studies provide evidence that Met dysregulation may play a role in the biology of canine cancer and lay the groundwork for future studies employing Met inhibitors.
Insights
Met dysregulation is implicated in canine cancers. This study cloned canine Met, HGF, and HGF activator, finding Met pathway activation in tumors and potential for Met inhibitor therapies.
Area of Science:
- Oncology
- Molecular Biology
- Veterinary Medicine
Background:
- Aberrant proto-oncogene c-Met expression is linked to human cancers.
- Met dysregulation's role in canine cancer requires further investigation.
Purpose of the Study:
- To clone canine Met, hepatocyte growth factor (HGF), and HGF activator.
- To investigate Met pathway activation and its role in canine tumor biology.
Main Methods:
- Cloning of canine Met, HGF, and HGF activator.
- Analysis of Met expression in canine tumor cell lines.
- Stimulation with recombinant human HGF and assessment of downstream signaling (Gab-1, Akt, Erk1/2).
- Inhibition studies using PHA665752, a Met inhibitor.
Main Results:
- Inappropriate Met expression was found in various canine tumor cell lines.
- Canine tumor cells expressed HGF and HGF activator, suggesting autocrine activation.
- HGF stimulation induced Met autophosphorylation and downstream signaling.
- HGF promoted tumor cell scattering and migration, which were blocked by PHA665752.
Conclusions:
- Met dysregulation may contribute to the biology of canine cancers.
- The Met signaling pathway is a potential therapeutic target in canine oncology.
- These findings support future research on Met inhibitors for canine cancer treatment.
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