Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, 1900 Coffey Road, 444 Veterinary Medical Academic Building, Columbus, OH, USA.
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA.
BMC Vet Res. 2021 Oct 2;17(1):320. doi: 10.1186/s12917-021-03027-0.
Urothelial carcinoma (UC) accounts for > 90% of canine tumors occurring in the urinary bladder. Toceranib phosphate (TOC) is a multi-target receptor tyrosine kinase (RTK) inhibitor that exhibits activity against members of the split kinase family of RTKs. The purpose of this study was to evaluate primary UC tumors and UC cell lines for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, and KIT to assess whether dysregulation of these RTKs may contribute to the observed biological activity of TOC.
Transcript for VEGFR2, PDGFRα, PDGFRβ, and KIT was detected in all UC tissue samples and UC cell lines. The Proteome Profiler™ Human Phospho-RTK Array Kit (R & D Systems) provided a platform to assess phosphorylation of 42 different RTKs in primary UC tumors and UC cell lines. Evidence of PDGFRα and PDGFRβ phosphorylation was present in only 11% or 33% of UC tumors, respectively, and 25% of UC cell lines. Treatment of UC cell lines with TOC had no significant impact on cell proliferation, including UC cell lines with evidence of PDGFRβ phosphorylation.
Phosphorylation of several key RTKs targeted by TOC is present in a small subset of primary UC tumors and UC cell lines, suggesting that these RTKs do not exist in a state of continuous activation. These data suggest that activation of RTKs targeted by TOC is present in a small subset of UC tumors and UC cell lines and that treatment with TOC at physiologically relevant concentrations has no direct anti-proliferative effect on UC cells.
尿路上皮癌（UC）占犬类膀胱肿瘤的 90%以上。磷酸托法替尼（TOC）是一种多靶点受体酪氨酸激酶（RTK）抑制剂，对 RTK 家族的分裂激酶家族成员具有活性。本研究旨在评估原发性 UC 肿瘤和 UC 细胞系中 VEGFR2、PDGFRα、PDGFRβ 和 KIT 的表达和激活情况，以评估这些 RTK 的失调是否可能导致 TOC 观察到的生物学活性。
所有 UC 组织样本和 UC 细胞系中均检测到 VEGFR2、PDGFRα、PDGFRβ 和 KIT 的转录本。Proteome Profiler™ 人类磷酸化 RTK 阵列试剂盒（R & D Systems）提供了一个平台，可用于评估原发性 UC 肿瘤和 UC 细胞系中 42 种不同 RTK 的磷酸化。PDGFRα 和 PDGFRβ 磷酸化的证据分别仅存在于 11%或 33%的 UC 肿瘤中，25%的 UC 细胞系中。TOC 对 UC 细胞系的治疗对细胞增殖没有显著影响，包括具有 PDGFRβ 磷酸化证据的 UC 细胞系。
在一小部分原发性 UC 肿瘤和 UC 细胞系中存在 TOC 靶向的几个关键 RTK 的磷酸化，表明这些 RTK 不存在持续激活的状态。这些数据表明，TOC 靶向的 RTK 的激活存在于一小部分 UC 肿瘤和 UC 细胞系中，并且 TOC 在生理相关浓度下的治疗对 UC 细胞没有直接的抗增殖作用。
