Analysis of genomic mutation and immunohistochemistry of platelet‐derived growth factor receptors in canine vascular tumours

Abou, Samah; Mori, Takashi; Maruo, Keishi; Khater, A. R.; Elsawak, Ahmed; el-Aziz, E. Abd; Yanai, Tokuma; Sakai, Hiroki

doi:10.1111/vco.12035

Cited by 13 publications

(16 citation statements)

References 29 publications

(29 reference statements)

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“…Even if an autocrine receptor activation may occur in T-cell lymphomas, it is still not known if this is a critical or a contributing event in its development. Also, structural aberrations of PDGFRs that lead to overexpression or expression of abnormal proteins have been described in canine vascular tumours (Abou Asa et al, 2013), and will be taken into consideration in the next studies. PDGF-B and PDGFRs may represent new therapeutic target in canine T-cell lymphomas and future studies will be directed to collect clinical data to further understand a potential prognostic role of these molecules.…”

Section: Discussionmentioning

confidence: 99%

Platelet-derived Growth Factors and Receptors in Canine Lymphoma

Aricò

Guadagnin

Ferraresso

et al. 2014

Journal of Comparative Pathology

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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.

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Section: Discussionmentioning

confidence: 99%

Platelet-derived Growth Factors and Receptors in Canine Lymphoma

Aricò

Guadagnin

Ferraresso

et al. 2014

Journal of Comparative Pathology

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“…In dogs, a recent whole-exome sequencing study of a small cohort of 20 angiosarcomas showed that the top recurrently mutated genes were PIK3CA and TP53 (29) . Earlier candidate gene studies of canine angiosarcomas have reported mutations in TP53 (30) , PTEN (31) , and PDGFRA and PDGFRB (32) . An analysis of somatic copy number aberrations in visceral angiosarcomas from five breeds found that VEGFA showed frequent copy number gain, while CDKN2A was frequently deleted (33) .…”

Section: Introductionmentioning

confidence: 98%

Genomic analysis reveals shared genes and pathways in human and canine angiosarcoma

Megquier

Turner-Maier

Swofford

et al. 2019

Preprint

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Angiosarcoma is a highly aggressive cancer of blood vessel-forming cells with high fatality and few effective treatment options. It is both rare and heterogenous, making large, well powered genomic studies nearly impossible. In dogs, angiosarcoma is common, with breeds like the golden retriever carrying heritable genetic factors that put them at very high risk. If the clinical similarity of canine and human angiosarcoma reflects shared genomic etiology, dogs could be a critically needed model for advancing angiosarcoma research. We assessed the genomic landscape of canine angiosarcoma via whole exome sequencing (47 golden retriever angiosarcomas) and RNA sequencing (74 angiosarcomas from multiple breeds). The predominant mutational signature was the age-associated deamination of cytosine to thymine, and somatic coding mutations occurred most frequently in the tumor suppressor TP53 (59.6% of cases) as well as two genes in the PI3K pathway: the oncogene PIK3CA (29.8%) and its regulatory subunit PIK3R1 (8.5%). We compared the canine data to human data recently released by The Angiosarcoma Project, and found the same genes and many of the same pathways significantly enriched for somatic mutations, most notably protein kinases, glycoproteins, fibronectin Type III domains, EGF-like domains, and cell adhesion proteins such as cadherins. As in human angiosarcoma, CDKN2A/B was recurrently deleted and VEGFA, KDR, and KIT recurrently gained. Canine angiosarcoma closely models human angiosarcoma on a genomic level, and is a powerful tool for investigating the pathogenesis of this devastating disease. Canine only PI3K pathway PIK3CG

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“…This is again reflected in the relatively lower median expression score of 54.6 compared with VEGFR expression. The predominant PDGFR expression pattern in the current study was cytoplasmic (PDGFR‐α, 87.9%; PDGFR‐β, 63.5%) as already reported in previous studies with canine vascular tumours . Interestingly, this study also demonstrated a strong stromal expression for both PDGFRs (PDGFR‐α in 15.5%; PDGFR‐β in 60.9%) as compared with VEGFR (8.5%).…”

Section: Discussionmentioning

confidence: 55%

Expression of VEGFR and PDGFR‐α/‐βin 187 canine nasal carcinomas

Gramer

Killick

Scase

et al. 2016

Vet Comparative Oncology

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Radiotherapy represents the standard of care for intranasal carcinomas. Responses to tyrosine kinase inhibitors (TKIs) have been reported but data on expression of target receptor tyrosine kinases (rTKs) is limited. This study characterizes the expression of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR)-α and PDGFR-β in canine intranasal carcinomas. Histological samples from 187 dogs were retrieved. Immunohistochemistry was performed using commercially available antibodies. Expression of rTKs was classified into weak, moderate or intense and additionally recorded as cytoplasmic, membranous, cytoplasmic-membranous, nuclear or stromal. VEGFR was expressed in 158 dogs with predominantly moderate expression (36.9%) and a cytoplasmic-membranous expression pattern (70.9%). PDGFR-α was detected in 133 with predominantly weak expression (57.9%) and cytoplasmic pattern (87.9%). PDGFR-β was identified in 74 patients with a predominantly moderate expression (17.6%) and cytoplasmic expression pattern (63.5%). Co-expression of rTKs was common. These results confirm expression of VEGFR, PDGFR-α and PDGFR-β in canine intranasal carcinomas and support the utility of TKIs.

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Analysis of genomic mutation and immunohistochemistry of platelet‐derived growth factor receptors in canine vascular tumours

Cited by 13 publications

References 29 publications

Platelet-derived Growth Factors and Receptors in Canine Lymphoma

Platelet-derived Growth Factors and Receptors in Canine Lymphoma

Genomic analysis reveals shared genes and pathways in human and canine angiosarcoma

Expression of VEGFR and PDGFR‐α/‐βin 187 canine nasal carcinomas

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