Hippo信号通路参与乳腺癌和犬乳腺肿瘤(CMT)。本研究旨在评估氟伐他汀对Hippo通路及其主要效应子的疗效。YAP和TAZ,在小鼠CMT细胞系异种移植模型中的体内。在治疗第1天,将小鼠分为四组:媒介物,氟伐他汀,阿霉素或联合治疗。在处理的第28天用卡尺和收获的组织监测肿瘤体积。进行肿瘤组织和主要器官的组织病理学检查以及肿瘤坏死的评估,凋亡,细胞增殖,YAP的表达,TAZ及其四个靶基因(CTGF,CYR61、ANKRD1和RHAMM2)。结果显示,与对照相比,仅联合治疗的肿瘤体积和仅阿霉素组的最终肿瘤重量的统计学显著变化。肿瘤坏死没有显着差异,通过免疫组织化学和靶基因mRNA水平测量CC3,ki-67,YAP和TAZ的表达。出乎意料的是,在对照组(9)和氟伐他汀治疗组未发现肺转移(7)。此外,基于质谱的氟伐他汀定量显示的浓度与报道的发挥治疗作用的水平相当.这项研究表明,氟伐他汀肿瘤浓度达到治疗水平,对hippo途径或各种肿瘤参数没有影响。有趣的是,只有对照组有肺转移.本研究首次探索他汀类药物在兽医癌症治疗中的再利用。
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.