Immunohistochemical Analysis of the Akt/mTOR/4E-BP1 Signalling Pathway in Canine Haemangiomas and Haemangiosarcomas

Murai, Atsuko; Abou, Samah; Kodama, Atsushi; Sakai, Hiroki; Hirata, Akihiro; Yanai, Tokuma

doi:10.1016/j.jcpa.2012.05.002

Cited by 22 publications

(18 citation statements)

References 29 publications

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“…To validate the functional relevance of the canine PIK3CA and NRAS mutants, we performed immunohistochemistry for phospho-ERK, phospho-AKT, and phopsho-S6. p-ERK is a wellestablished downstream effector of MAPK signaling, while p-AKT and p-S6 are classic markers of PI3K/AKT/ mTOR pathway activation [19,20]. Indeed, out of 8 NRAS-mutant cases that we tested by IHC, 7 showed diffuse and intense nuclear-cytoplasmic immunoreactivity for p-ERK1/2 Thr202/Tyr204 (Fig 6A).…”

Section: Mutations In Pik3ca and Nras Trigger Activation Of Downstreamentioning

confidence: 93%

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Wang

Durham

et al. 2020

PLoS ONE

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Angiosarcoma (AS) is a rare neoplasm with limited treatment options and a poor survival rate. Development of effective therapies is hindered by the rarity of this disease. Dogs spontaneously develop hemangiosarcoma (HSA), a common, histologically similar neoplasm. Metastatic disease occurs rapidly and despite chemotherapy, most dogs die several months after diagnosis. These features suggest that HSA might provide a tractable model to test experimental therapies in clinical trials. We previously reported whole exome sequencing of 20 HSA cases. Here we report development of a NGS targeted resequencing panel to detect driver mutations in HSA and other canine tumors. We validated the panel by resequencing the original 20 cases and sequenced 30 additional cases. Overall, we identified potential driver mutations in over 90% of the cases, including well-documented (in human cancers) oncogenic mutations in PIK3CA (46%), PTEN (6%), PLCG1(4%), and TP53 (66%), as well as previously undetected recurrent activating mutations in NRAS (24%). The driver role of these mutations is further demonstrated by augmented downstream signaling crucial to tumor growth. The recurrent, mutually exclusive mutation patterns suggest distinct molecular subtypes of HSA. Driver mutations in some subtypes closely resemble those seen in some AS cases, including NRAS, PLCG1, PIK3CA and TP53. Furthermore, activation of the MAPK and PI3K pathways appear to be key oncogenic mechanisms in both species. Together, these observations suggest that dogs with spontaneous HSA could serve as a useful model for testing the efficacy of targeted therapies, some of which could potentially be of therapeutic value in AS.

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Section: Mutations In Pik3ca and Nras Trigger Activation Of Downstreamentioning

confidence: 93%

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Wang

Durham

et al. 2020

PLoS ONE

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“…Importantly, some studies have reported that AKT and ERK signaling pathways are involved in the pathogenesis of canine haemangiomas 16 and cerebral cavernous malformation. 17 Blockade of these pathways may suppress cell proliferation and induce apoptosis and cycle arrest in proliferative phase HemECs.…”

Section: Introductionmentioning

confidence: 99%

Knockdown of VEGFR2 inhibits proliferation and induces apoptosis in hemangioma-derived endothelial cells

Ou¹,

Yu²,

Qiu³

et al. 2014

Eur J Histochem

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Angiogenesis is a process of development and growth of new capillary blood vessels from pre-existing vessels. Angiogenic growth factors play important roles in the development and maintenance of some malignancies, of which vascular endothelial growth factor (VEGF)/VEGFR2 interactions are involved in proliferation, migration, and survival of many cancer cells. The aim of this study was to investigate the function of VEGFR2 in human hemangiomas (HAs). Using immunohistochemistry assay, we examined the expression levels of VEGF, VEGFR2, Ki-67, glucose transporter-1 (Glut-1), phosphorylated protein kinase B (p-AKT) and p-ERK in different phases of human HAs. Positive expression of VEGF, VEGFR2, Ki-67, Glut-1, p-AKT and p-ERK was significantly increased in proliferating phase HAs, while decreased in involuting phase HAs (P=0.001; P=0.003). In contrast, cell apoptotic indexes were decreased in proliferating phase HAs, but increased in involuting phase HAs (P<0.01). Furthermore, we used small hairpin RNA (shRNA)-mediated VEGFR2 knockdown in primary HA-derived endothelial cells (HemECs) to understand the role of VEGF/VEGFR2 signaling. Knockdown of VEGFR2 by Lv-shVEGFR2 inhibited cell viability and induced apoptosis in primary HemECs companied with decreased expression of p-AKT, p-ERK, p-p38MAPK and Ki-67 and increased expression of caspase-3 (CAS-3); Overexpression of VEGFR2 promoted cell viability and blocked apoptosis in Lv-VEGFR2-transfected HemECs. Taken together, our findings demonstrate that, increased expression of VEGFR2 is involved in the development of primary HemECs possibly through regulation of the AKT and ERK pathways, suggesting that VEGFR2 may be a potential therapeutic target for HAs.

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“…The mTOR pathway is present and active in various immortalized canine cell lines such as osteosarcoma, 9 hemangiosarcoma, 10,11 and malignant melanoma. 12 Exposure of those cell lines to rapamycin results in a significant, dose-dependent decrease in viable tumor cells.…”

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confidence: 99%

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Larson

Allstadt

Fan

et al. 2016

ajvr

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Objective To determine the pharmacokinetics of orally administered rapamycin in healthy dogs. Animals 5 healthy purpose-bred hounds. Procedures The study consisted of 2 experiments. In experiment 1, each dog received rapamycin (0.1 mg/kg, PO) once; blood samples were obtained immediately before and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after administration. In experiment 2, each dog received (0.1 mg/kg, PO) once daily for 5 days; blood samples were obtained immediately before and at 3, 6, 24, 27, 30, 48, 51, 54, 72, 75, 78, 96, 96.5, 97, 98, 100, 102, 108, 120, 144, and 168 hours after the first dose. Blood rapamycin concentration was determined by a validated liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters were determined by compartmental and non-compartmental analyses. Results Mean ± SD blood rapamycin terminal half-life, area under the concentration-time curve from 0 to 48 hours after dosing, and maximum concentration were 38.7 ± 12.7 h, 140 ± 23.9 ng•h/mL, and 8.39 ± 1.73 ng/mL, respectively, for experiment 1, and 99.5 ± 89.5 h, 126 ± 27.1 ng•h/mL, and 5.49 ± 1.99 ng/mL, respectively, for experiment 2. Pharmacokinetic parameters for rapamycin after administration of 5 daily doses differed significantly from those after administration of 1 dose. Conclusions and Clinical Relevance Results indicated that oral administration of low-dose (0.1 mg/kg) rapamycin to healthy dogs achieved blood concentrations measured in ng/mL. The optimal dose and administration frequency of rapamcyin required to achieve therapeutic effects in tumor-bearing dogs, as well as toxicity after chronic dosing, needs to be determined.

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Immunohistochemical Analysis of the Akt/mTOR/4E-BP1 Signalling Pathway in Canine Haemangiomas and Haemangiosarcomas

Cited by 22 publications

References 29 publications

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Knockdown of VEGFR2 inhibits proliferation and induces apoptosis in hemangioma-derived endothelial cells

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

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