Department of Pathobiology, University of Pennsylvania, Philadelphia, PA.
Department of Safety Assessment, Genentech, South San Francisco, CA.
J Histochem Cytochem. 2021 Mar;69(3):203-218. doi: 10.1369/0022155420977970. Epub 2020 Dec 7.
The mouse line carrying the Tg(Tyr-NRASQ61K)1Bee transgene is widely used to model in vivo -driven melanomagenesis. Although the pathological features of this model are well described, classification and interpretation of the resulting proliferative lesions-including their origin, evolution, grading, and pathobiological significance-are still unclear and not supported by molecular and biological evidence. Focusing on their classification and grading, this work combines histopathology and expression analysis (using both immunohistochemistry [IHC] and quantitative PCR) of selected biomarkers to study the full spectrum of cutaneous and lymph nodal melanocytic proliferations in the Tg(Tyr-NRASQ61K)1Bee mouse. The analysis of cutaneous and lymph nodal melanocytic proliferations has demonstrated that a linear correlation exists between tumor grade and Ki-67, microphthalmia-associated transcription factor (MITF), gp100, and nestin IHC, with a significantly increased expression in high-grade lesions compared with low-grade lesions. The accuracy of the assessment of MITF IHC in melanomas was also confirmed by quantitative PCR analysis. In conclusion, we believe the incorporation of MITF, Ki-67, gp100, and nestin analysis into the histopathological classification/grading scheme of melanocytic proliferations described for this model will help to assess with accuracy the nature and evolution of the phenotype, monitor disease progression, and predict response to experimental treatment or other preclinical manipulations.
携带 Tg(Tyr-NRASQ61K)1Bee 转基因的小鼠系被广泛用于体内驱动黑素瘤发生的模型。尽管该模型的病理学特征已有详细描述，但对由此产生的增殖性病变的分类和解释——包括其起源、演变、分级和病理生物学意义——仍不清楚，也没有分子和生物学证据支持。本研究聚焦于其分类和分级，结合组织病理学和选定生物标志物的表达分析（包括免疫组织化学 [IHC] 和定量 PCR），研究了 Tg(Tyr-NRASQ61K)1Bee 小鼠皮肤和淋巴结黑素细胞增殖的全貌。对皮肤和淋巴结黑素细胞增殖的分析表明，肿瘤分级与 Ki-67、小眼畸形相关转录因子（MITF）、gp100 和巢蛋白 IHC 之间存在线性相关性，与低级别病变相比，高级别病变的表达显著增加。MITF IHC 评估黑色素瘤的准确性也通过定量 PCR 分析得到了证实。总之，我们认为将 MITF、Ki-67、gp100 和巢蛋白分析纳入该模型中描述的黑素细胞增殖的组织病理学分类/分级方案中，将有助于准确评估表型的性质和演变，监测疾病进展，并预测对实验治疗或其他临床前操作的反应。
