Département de Pathologie et de Microbiologie, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
Département de Biomédecine Vétérinaire, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, Québec, Canada.
Vet Comp Oncol. 2023 Dec;21(4):634-645. doi: 10.1111/vco.12926. Epub 2023 Sep 14.
The Hippo signalling pathway is involved in breast cancer and canine mammary tumour (CMT). This study sought to evaluate the efficacy of fluvastatin on the Hippo pathway and its main effectors, YAP and TAZ, in vivo in a murine CMT cell line xenograft model. On treatment day 1, mice were divided into four groups: vehicle, fluvastatin, doxorubicin or a combination therapy. Tumour volumes were monitored with callipers and tissues harvested on day 28th of treatment. Histopathological examination of tumour tissues and major organs was performed as well as tumour evaluation of necrosis, apoptosis, cellular proliferation, expression of YAP, TAZ and the mRNA levels of four of their target genes (CTGF, CYR61, ANKRD1 and RHAMM2). Results showed a statistically significant variation in tumour volumes only for the combination therapy and final tumour weight only for the doxorubicin group compared to control. There was no significant difference in tumour necrosis, expression of CC3, ki-67, YAP and TAZ measured by immunohistochemistry and in the mRNA levels of the target genes. Unexpectedly, lung metastases were found in the control group (9) and not in the fluvastatin treated group (7). In addition, mass spectrometry-based quantification of fluvastatin reveals concentrations comparable to levels reported to exert therapeutic effects. This study shows that fluvastatin tumours concentration reached therapeutic levels without having an effect on the hippo pathway or various tumour parameters. Interestingly, only the control group had lung metastases. This study is the first to explore the repurposing of statins for cancer treatment in veterinary medicine.
Hippo 信号通路与乳腺癌和犬乳腺肿瘤（CMT）有关。本研究旨在评估氟伐他汀在体内对 Hippo 通路及其主要效应物 YAP 和 TAZ 的影响，采用的是一种鼠 CMT 细胞系异种移植模型。在治疗第 1 天，将小鼠分为四组：对照组、氟伐他汀组、阿霉素组和联合治疗组。通过卡尺监测肿瘤体积，并在治疗第 28 天采集组织。对肿瘤组织和主要器官进行组织病理学检查，并对肿瘤坏死、凋亡、细胞增殖、YAP、TAZ 表达以及它们的四个靶基因（CTGF、CYR61、ANKRD1 和 RHAMM2）的 mRNA 水平进行评估。结果显示，与对照组相比，只有联合治疗组的肿瘤体积和阿霉素组的最终肿瘤重量有统计学上的显著差异。免疫组化检测的肿瘤坏死、CC3、ki-67、YAP 和 TAZ 表达以及靶基因的 mRNA 水平均无显著差异。出乎意料的是，对照组（9 例）出现肺转移，而氟伐他汀治疗组（7 例）未出现肺转移。此外，基于质谱的氟伐他汀定量分析显示，其在肿瘤中的浓度达到了治疗水平，而对 hippo 通路或各种肿瘤参数没有影响。有趣的是，只有对照组出现了肺转移。本研究首次在兽医肿瘤学领域探索了将他汀类药物重新用于癌症治疗。
