Constitutive phosphorylation of the mTORC2/Akt/4E-BP1 pathway in newly derived canine hemangiosarcoma cell lines

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

doi:10.1186/1746-6148-8-128

Cited by 53 publications

(65 citation statements)

References 48 publications

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“…p-S6 is expressed in cases with PIK3CA or PTEN mutations (Fig 6B), indicating activation of the PI3K/AKT/mTOR cascade. Our findings agree with previous studies which showed that the PI3K and MAPK pathway were frequently activated in canine HSA [20,22], and our mutational data provide molecular mechanisms for these phenotypes. IHC analysis of p-ERK, p-AKT and p-S6 in HSA cases is summarized in S3 Table.…”

Section: Plos Onesupporting

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: Plos Onesupporting

confidence: 93%

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Wang

Durham

et al. 2020

PLoS ONE

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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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“…29 Furthermore, a total of seven canine AS cell lines were established from three different xenograft canine tumors. 30 Although there are a number of AS cell lines derived from cutaneous tumors, so far only one cell line has been generated from hepatic AS. 31 This cell line named HAEND was established from a post-mortem liver biopsy of a patient diagnosed with hepatic AS induced by vinyl chloride, a well-known causal agent.…”

Section: Discussionmentioning

confidence: 99%

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

Rothweiler¹,

Dill²,

Terracciano

et al. 2015

Laboratory Investigation

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Hepatic angiosarcoma (AS) is a rare and highly aggressive tumor of endothelial origin with dismal prognosis. Studies of the molecular biology of AS and treatment options are limited as animal models are rare. We have previously shown that inducible knockout of Notch1 in mice leads to spontaneous formation of hepatic AS. The aims of this study were to: (1) establish and characterize a cell line derived from this murine AS, (2) identify molecular pathways involved in the pathogenesis and potential therapeutic targets, and (3) generate a tumor transplantation model. AS cells retained specific endothelial properties such as tube formation activity, as well as expression of CD31 and Von Willebrand factor. However, electron microscopy analysis revealed signs of dedifferentiation with loss of fenestrae and loss of contact inhibition. Microarray and pathway analysis showed substantial changes in gene expression and revealed activation of the Myc pathway. Exposing the AS cells to sorafenib reduced migration, filopodia dynamics, and cell proliferation but did not induce apoptosis. In addition, sorafenib suppressed ERK phosphorylation and expression of cyclin D2. Injection of AS cells into NOD/SCID mice resulted in formation of undifferentiated tumors, confirming the tumorigenic potential of these cells. In summary, we established and characterized a murine model of spontaneous AS formation and hepatic AS cell lines as a useful in vitro tool. Our data demonstrate antitumor activity of sorafenib in AS cells with potent inhibition of migration, filopodia formation, and cell proliferation, supporting further evaluation of sorafenib as a novel treatment strategy. In addition, AS cell transplantation provides a subcutaneous tumor model useful for in vivo preclinical drug testing.

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Constitutive phosphorylation of the mTORC2/Akt/4E-BP1 pathway in newly derived canine hemangiosarcoma cell lines

Cited by 53 publications

References 48 publications

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma

Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

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