Department of Pathology and Infectious Diseases, School of Veterinary Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
J Vet Diagn Invest. 2023 Mar;35(2):109-115. doi: 10.1177/10406387221146247. Epub 2023 Jan 17.
Urothelial carcinomas (UCs), also known as transitional cell carcinomas, are the most common canine urinary tract neoplasms. Tyrosine kinases (TKs) are enzymes that tightly regulate cell growth and differentiation through phosphorylation. Receptor TK (RTK) inhibitors are currently used to treat UCs. Toceranib phosphate (Palladia; Pfizer) is an RTK inhibitor that blocks the activity of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor-alpha and -beta (PDGFR-α, -β), FMS-like tyrosine kinase 3, stem cell factor receptor (KIT, kinase inhibitor targeting), and colony stimulating factor receptor. To better understand UCs and validate treatment targets, we performed immunohistochemical staining for RTKs, as well as a novel target, cyclin-dependent kinase 4 (CDK4, a central regulator of the mammalian cell cycle), on formalin-fixed, paraffin-embedded tissues from bladder biopsies from 17 dogs with UCs, 17 dogs with cystitis (diseased controls), and 8 normal dogs (negative controls). Although immunohistochemical scores could not be extrapolated to prognostic value, response to treatment, and outcome of patients with UC, we demonstrated expression of PDGFR-β and VEGFR2 in UCs; all UC samples staining positively for VEGFR2. Minimal positive staining for KIT was noted in the tumor samples. CDK4 staining intensity was significantly weaker in UCs compared with normal and cystitis bladder samples. The intense staining of VEGFR2 in UC cells suggested that VEGFR2 may be of prognostic and/or therapeutic value in dogs with UC. Overexpression of VEGFR2 in UC cells validates this receptor as a treatment target in UC.
尿路上皮癌（UCs），也称为移行细胞癌，是犬最常见的泌尿道肿瘤。酪氨酸激酶（TKs）是通过磷酸化紧密调节细胞生长和分化的酶。受体酪氨酸激酶（RTK）抑制剂目前用于治疗 UCs。托西尼布磷酸盐（Palladia；辉瑞）是一种 RTK 抑制剂，可阻断血管内皮生长因子受体 2（VEGFR2）、血小板衍生生长因子受体-α和-β（PDGFR-α、-β）、FMS 样酪氨酸激酶 3、干细胞因子受体（KIT，激酶抑制剂靶向）和集落刺激因子受体的活性。为了更好地了解 UCs 并验证治疗靶点，我们对来自 17 只患有 UCs 的犬、17 只患有膀胱炎（疾病对照）和 8 只正常犬（阴性对照）的膀胱活检组织进行了 RTK 以及新型靶标细胞周期蛋白依赖性激酶 4（CDK4，哺乳动物细胞周期的中央调节剂）的免疫组织化学染色。虽然免疫组织化学评分不能外推到预后价值、治疗反应和 UCs 患者的结果，但我们在 UCs 中证实了 PDGFR-β和 VEGFR2 的表达；所有 UCs 样本均对 VEGFR2 呈阳性染色。在肿瘤样本中仅观察到 KIT 的微弱阳性染色。与正常和膀胱炎膀胱样本相比，UC 中的 CDK4 染色强度明显较弱。UC 细胞中 VEGFR2 的强烈染色表明 VEGFR2 可能对患有 UC 的犬具有预后和/或治疗价值。UC 细胞中 VEGFR2 的过表达验证了该受体作为 UC 治疗靶点的有效性。
