Platelet-derived Growth Factors and Receptors in Canine Lymphoma

Abstract

Platelet-derived growth factors (PDGFs) belong to a family of polypeptide growth factors that signal through cell surface tyrosine kinase receptors to stimulate growth, proliferation and differentiation. Platelet-derived growth factor receptors (PDGFRs) are also considered important targets for specific kinase inhibitors in the treatment of several human tumours. The aim of this study was to investigate the role of PDGF-A, PDGF-B, PDGFR-α and PDGFR-β in canine lymphoma by determining gene and protein expression in lymph nodes of dogs with diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma (PTCL), T-lymphoblastic lymphoma (T-LBL) and in healthy control dogs. One lymph node was also studied at the end of therapy in a subset of dogs in remission for DLBCL. In controls, PDGF-A, PDGFR-α and PDGFR-β mRNA levels were significantly higher than in DLBCLs, PTCLs and T-LBLs. However, PDGFR-α and PDGFR-β were minimally expressed by lymphocytes and plasma cells in normal lymph nodes as determined by immunohistochemistry, while neoplastic B and T cells showed the highest score (P <0.05). This discordant result may be compatible with the constitutive expression of these molecules by endothelial cells and fibroblasts in normal lymph nodes, thereby influencing gene expression results. Furthermore, these cells were not included in the immunohistochemical analysis. Similarly, dogs with DLBCL that were in remission at the end of therapy showed significantly higher gene expression of PDGFs and receptors than at the time of diagnosis and with an opposite trend to the protein assay. PDGF-B protein and mRNA were overexpressed in PTCLs and T-LBLs when compared with DLBCLs and controls (P <0.05). Additionally, there was a correlation between protein expression of PDGF-B and both PDGFRs in PTCLs and T-LBLs, suggesting an autocrine or paracrine loop in the aetiology of aggressive canine T-cell lymphomas. These data provide a rationale for the use of PDGFR antagonists in the therapy of aggressive T-cell lymphomas, but not in DLBCLs.

PDGFRs expression in dogs affected by malignant oral melanomas: correlation with prognosis

“…In domestic animal tumours, the IHC expression of PDGFRs has been investigated in astrocytoma, lymphoma, osteosarcoma, anal sac adenocarcinoma, thyroid carcinoma and haemangiosarcoma, highlighting the importance of these receptors also in the tumour biology of animals, as it occurs in humans . However, for none of these tumours a prognostic relevance has been demonstrated.…”

Effects of toceranib phosphate (Palladia) monotherapy on multidrug resistant lymphoma in dogs

“…It has been reported that this resistance is facilitated by the activation of P-glycoprotein (P-gp), other drug transporters, or a combination of both [ 18 ]. Angiogenesis is required for the survival of hematologic cancers [ 20 ] and the expression patterns of angiogenic growth factors, including platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR), correlate with clinical stage and historical grade in canine lymphoma [ 2 , 15 ]. Additionally, overexpression of PDGFR and VEGFR promotes resistance to several anti-cancer drugs [ 1 , 14 ].…”

Hypoxia-activated prodrug TH-302 decreased survival rate of canine lymphoma cells under hypoxic condition

“…Several research groups have reported that elevated HIF-1α levels have been linked to poor prognoses in human diffuse large-B-cell lymphoma [20, 21]. Other groups suggested that the expression patterns of PDGF, VEGF and survivin in canine lymphoma correlate with clinical stage and histological grade [19, 22, 23]. Hypoxic stimulation effectively may improve growth potential and invasiveness of canine lymphoma cells in response to upregulation of PDGF , VEGF and survivin expression.…”