Fowles J S, Denton C L, Gustafson D L
Cell and Molecular Biology Program, Department of Clinical Sciences, Colorado State University, Fort Collins, CO, USA.
Flint Animal Cancer Center, Veterinary Medical Center, Colorado State University, Fort Collins, CO, USA.
Vet Comp Oncol. 2015 Sep;13(3):288-304. doi: 10.1111/vco.12044. Epub 2013 Jun 7.
The lack of advanced animal models of human cancers is considered a barrier to developing effective therapeutics. Canine and human melanomas are histologically disparate but show similar disease progression and response to therapies. The purpose of these studies was to compare human and canine melanoma tumours and cell lines regarding MAPK and PI3K/AKT signalling dysregulation, and response to select molecularly targeted agents. Pathway activation was investigated via microarray and mutational analysis. Growth inhibition and cell cycle effects were assessed for pathway inhibitors AZD6244 (MAPK) and rapamycin (PI3K/AKT) in human and canine melanoma cells. Human and canine melanoma share similar differential gene expression patterns within the MAPK and PI3K/AKT pathways. Constitutive pathway activation and similar sensitivity to AZD6244 and rapamycin was observed in human and canine cells. These results show that human and canine melanoma share activation and sensitivity to inhibition of cancer-related signalling pathways despite differences in activating mutations.
缺乏先进的人类癌症动物模型被认为是开发有效治疗方法的一个障碍。犬类和人类黑色素瘤在组织学上存在差异，但显示出相似的疾病进展和对治疗的反应。这些研究的目的是比较人类和犬类黑色素瘤肿瘤及细胞系在MAPK和PI3K/AKT信号失调方面的情况，以及对选定分子靶向药物的反应。通过微阵列和突变分析来研究通路激活情况。评估了通路抑制剂AZD6244（MAPK）和雷帕霉素（PI3K/AKT）对人类和犬类黑色素瘤细胞的生长抑制和细胞周期影响。人类和犬类黑色素瘤在MAPK和PI3K/AKT通路内具有相似的差异基因表达模式。在人类和犬类细胞中观察到组成型通路激活以及对AZD6244和雷帕霉素的相似敏感性。这些结果表明，尽管激活突变存在差异，但人类和犬类黑色素瘤在癌症相关信号通路的激活和对抑制的敏感性方面具有共性。
