JVDI in Focus

Our February focus is an article appearing in JVDI’s March issue, “Immunohistochemical analysis of expression of VEGFR2, KIT, PDGFR-β, and CDK4 in canine urothelial carcinoma” by Laura C. Setyo, Shannon L. Donahoe, Patrick L. Shearer, Penghao Wang, Mark B. Krockenberger.

J Vet Diagn Invest 2023;35(2). https://journals.sagepub.com/doi/epdf/10.1177/10406387221146247

Abstract. 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.

Figures 1–6. Immunohistochemical expression of VEGFR2, KIT, PDGFR-β, and CDK4 in canine urothelial carcinoma (UC). Figures 1–3. Immunolabeling for transitional epithelium in normal canine urinary bladder. Diaminobenzidine (DAB) chromogen, hematoxylin counterstain. Figure 1. CDK4 cytoplasmic and nuclear immunoreactivity is mild and diffuse. Figure 2. FLK (VEGFR2) cytoplasmic immunoreactivity is intense and diffuse. Figure 3. KIT immunoreactivity is absent. Figures 4–6. Immunolabeling for transitional epithelium in canine UC. DAB chromogen, hematoxylin counterstain. Figure 4. CDK4 immunoreactivity is absent. Figure 5. Neoplastic cells have intense and diffuse cytoplasmic immunolabeling for VEGFR2. Figure 6. KIT immunoreactivity is absent.

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