Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms

Willmann, Michael; Hadzijusufovic, Emir; Hermine, Olivier; Dacasto, Mauro; Marconato, Laura; Bauer, Karin; Peter, Barbara; Gamperl, Susanne; Eisenwort, Gregor; Jensen‐Jarolim, Erika; Müller, Mathias; Arock, Michel; Vail, David M.; Valent, Peter

doi:10.1111/vco.12440

Cited by 23 publications

(22 citation statements)

References 102 publications

(218 reference statements)

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“…At present, the only curative treatment approach is wide‐margin surgery . If a complete resection is not possible or if a tumour recurs, radio‐ and/or chemotherapy are usually offered . Recently, masitinib and toceranib, two targeted drugs directed against proto‐oncogene, receptor tyrosine kinase (KIT), have been approved for therapy of non‐resectable or metastasized high‐grade MCT .…”

Section: Introductionmentioning

confidence: 99%

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

Gamperl

Stefanzl

Peter

et al. 2019

Vet Comparative Oncology

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The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is effective in the treatment of human chronic lymphocytic leukaemia and mantle cell lymphoma. Recent data have shown that ibrutinib also blocks IgE‐dependent activation and histamine release in human basophils (BAs) and mast cells (MCs). The aim of this study was to investigate whether BTK serves as a novel therapeutic target in canine mast cell tumours (MCTs). We evaluated the effects of ibrutinib on two canine MC lines, C2 and NI‐1 and on primary MCs obtained from canine MCTs (n = 3). Using flow cytometry, we found that ibrutinib suppresses phosphorylation of BTK and of downstream STAT5 in both MC lines. In addition, ibrutinib decreased proliferation of neoplastic MCs, with IC50 values ranging between 0.1 and 1 μM in primary MCT cells and between 1 and 3 μM in C2 and NI‐1 cells. In C2 cells, the combination “ibrutinib + midostaurin” produced synergistic growth‐inhibitory effects. At higher concentrations, ibrutinib also induced apoptosis in both MC lines. Finally, ibrutinib was found to suppress IgE‐dependent histamine release in primary MCT cells, with IC50 values ranging from 0.05 to 0.1 μM in NI‐1 cells, and from 0.05 to 1 μM in primary MCT cells. In summary, ibrutinib exerts anti‐proliferative effects in canine neoplastic MCs and counteracts IgE‐dependent histamine release in these cells. Based on our data, ibrutinib may be considered as a novel therapeutic agent for the treatment of canine MCT. The value of BTK inhibition in canine MCT patients remains to be elucidated in clinical trials.

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Section: Introductionmentioning

confidence: 99%

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

Gamperl

Stefanzl

Peter

et al. 2019

Vet Comparative Oncology

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“…Відповідно до сучасного трактування у гуманній медицині (Akin et al, 2010;Alvarez-Twose et al, 2016;Okhotnikova et al, 2018) САМ, обумовлений вивільненням медіаторів з активованих мастоцитів, об'єднує гетерогенну групу захворювань, які характеризуються клінічними ознаками ураження шкіри, слизових оболонок шлунково-кишкового тракту і дихальних шляхів, органів серцево-судинної та нервової систем, у тому числі й системними реакціями, зокрема, алергією та анафілаксією. Як свідчить аналіз літературних повідомлень (Willmann et al, 2018;Tamlin et al, 2020) перебіг захворювань, за безпосередньої участі активованих ОК, у людини та в тварин має певні відмінності. За даними медичної літератури (Frieri & Quershi, 2013;Valent et al, 2015;Gülen et al, 2016;Pardanani, 2016;Frolova et al, 2018;Leguit et al, 2020) на мастоцитоз частіше хворіють діти у яких хвороба перебігає у шкірній формі (зазвичай, як пігментна кропив'янка, рідше солітарна мастоцитома) і при досягненні пубертатного віку хвороба, як правило, регресує.…”

Section: мастоцитомаunclassified

“…Належно відмітити також, що спонтанні пухлини тварин відповідають багатьом критеріям новоутворень людини, а схожість етіології, патогенезу, симптоматики та морфології пухлин у собак і людини обумовлює використання тварин, як моделей для вивчення біології пухлинного процесу та розробки сучасних діагностичних і терапевтичних заходів (Willmann et al, 2018;Garden et al, 2018;Gargiulo, 2018).…”

Section: мастоцитомаunclassified

Clinical characteristics of mastocytoma in dogs

2020

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According to foreign researchers, mastocytoma is one of the most common (7-12 %) skin tumors in dogs. This neoplasia is caused by excessive proliferation of mast cells and characterized by a specific clinical course, unpredictable biological behavior and prognosis. Researches of clinical and morphological features of mastocytoma in geographical populations of Ukraine has not only scientific and general biological interest, but also important practical significance. The purpose of the research was to establish the frequency of spreading, the features of the clinical ostent and pathogenesis of cutaneous mastocytoma in dogs in conditions in Lviv and in the suburban zone of the regional center. The research was performed on dogs with skin tumors (n = 128), including 24 of them with mastocytoma, who came to the Department of Surgery and Clinic of Small Pets of Stepan Gzhytskyj LNUVMB during 2016–2020. The diagnosis on mastocytoma was verified by the results of physical examination and cytological examination of biopsy material of neoplasms. It was found that in the structure of oncological diseases of dogs the share of skin neoplasms was 32.16 %. Among animals with skin neoplasms, mastocytoma was diagnosed in 18.75 % of dogs aged 4 to 16 years. The highest incidence rates were found among animals aged 8 to 11 years; the median incidence was 9.5 years and fashion – 9 years. In terms of breeds, cutaneous mastocytoma was found in dogs of the breed: Rottweiler – 16.7 %, Sharpei – 12.5 %, Staffordshire Terrier – 12.5 %, Labrador – 8.3 %, Boxer – 8.3 %, Doberman – 8.3 %, chow-chow – 8.3 %. At the same time, the German Shepherd, Alabai, Spaniel, French Bulldog and Pug cases of the disease were isolated (4.2 %). Among sick animals, dogs accounted for 54.2 % and females for 45.8 %. It was found that in 41.7 % of the studied animals the rate of neoplasia was extremely rapid, because in 56.5 ± 1.91 days the tumors were doubled in size, which is evidence of significant aggressiveness of tumor growth. In 29.2 % of dogs the time of doubling the size of the primary tumor reached 122.1 ± 10.6 days, in 20.8 % of dogs the period of tumor development lasted for two years. In 8.3 % of dogs, the dynamics of neoplasia development is not clear. Sonography has shown that skin mastocytomas are usually visualized as heterogeneous, with uneven edges and fuzzy contours hypoechoic structures. Visualization of solid hypervascular foci with central type of vascularization, on the background of diffuse infiltration of neoplasia in the deeper layers of the skin and subcutaneous tissue, with a pronounced perinodular inflammatory reaction of the surrounding tissues is a sign of malignancy of the mastocytoma. The generalization of the neoplastic process in the internal organs was found, in particular the spleen, may indicate a predominance of the hematogenous route of metastasis of the mastocytoma. The obtained data complement and expand knowledge about the pathogenesis of mastocytoma in dogs, and also highlight the frequency of spreading and course features of this oncological pathology in a separate geographical population of Ukraine.

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“…First results indicate reduced proliferation and increased apoptosis upon inhibition of JAK1/2 or STAT3 respectively [115][116][117][118][119][120][121]. Two areas exemplify the potential of research and development concerning STAT proteins and human-canine comparative oncology best [122,123]. Osteosarcoma is the most frequent form of malignant bone disease in dogs, however, it is relatively rare in humans.…”

Section: Inhibition Of Stat3 and Stat5 In Companion Animals: Current mentioning

confidence: 99%

Companion Animals as Models for Inhibition of STAT3 and STAT5

Kieslinger

Swoboda

Kramer

et al. 2019

Cancers

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The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine.

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Comparative oncology: The paradigmatic example of canine and human mast cell neoplasms

Cited by 23 publications

References 102 publications

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

Effects of ibrutinib on proliferation and histamine release in canine neoplastic mast cells

Clinical characteristics of mastocytoma in dogs

Companion Animals as Models for Inhibition of STAT3 and STAT5

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