Mauda-Havakuk Michal, Mikhail Andrew S, Starost Matthew F, Jones Elizabeth C, Karim Baktiar, Kleiner David E, Partanen Ari, Esparza-Trujillo Juan A, Bakhutashvili Ivane, Wakim Paul G, Kassin Michael T, Lewis Andrew L, Karanian John W, Wood Bradford J, Pritchard William F
Center for Interventional Oncology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA.
J Hepatocell Carcinoma. 2021 Mar 9;8:71-83. doi: 10.2147/JHC.S287800. eCollection 2021.
Woodchucks chronically infected with woodchuck hepatitis virus (WHV), which resembles human hepatitis B virus, develop spontaneous hepatic tumors and may be an important biological and immunological model for human HCC. Nonetheless, this model requires further validation to fully realize its translational potential.
Woodchucks infected at birth with WHV that had developed HCC (n=12) were studied. Computed tomography, ultrasound, and magnetic resonance imaging were performed under anesthesia. LI-RADS scoring and correlative histologic analysis of sectioned tissues were performed. For immune characterization of tumors, CD3 (T cells), CD4 (T helpers), NCAM (Natural killers), FOXP3 (T-regulatory), PDL-1 (inhibitory checkpoint protein), and the human hepatocellular carcinoma (HCC) biomarker alpha-fetoprotein (AFP) immunohistochemical stains were performed.
Forty tumors were identified on imaging of which 29 were confirmed to be HCC with 26 categorized as LR-4 or 5. The remainder of the tumors had benign histology including basophilic foci, adenoma, and lipidosis as well as pre-malignant dysplastic foci. LR-4 and LR-5 lesions showed high sensitivity (90%) and specificity (100%) for malignant and pre-malignant tumors. Natural killers count was found to be 2-5 times lower in tumors relative to normal parenchyma while other immune cells were located in the periphery of tumors. Tumors expressed AFP and did not express PD-L1.
Woodchucks chronically infected with WHV developed diverse hepatic tumor types with diagnostic imaging, pathology, and immune patterns comparable to that in humans. This unique animal model may provide a valuable tool for translation and validation of novel image-guided and immune-therapeutic investigations.
土拨鼠慢性感染土拨鼠肝炎病毒（WHV），该病毒与人类乙型肝炎病毒相似，会自发形成肝肿瘤，可能是人类肝癌重要的生物学和免疫学模型。尽管如此，该模型需要进一步验证以充分发挥其转化潜力。
对出生时感染WHV且已发生肝癌的土拨鼠（n = 12）进行研究。在麻醉下进行计算机断层扫描、超声检查和磁共振成像。对切片组织进行LI-RADS评分和相关组织学分析。为了对肿瘤进行免疫特征分析，进行了CD3（T细胞）、CD4（辅助性T细胞）、NCAM（自然杀伤细胞）、FOXP3（调节性T细胞）、PDL-1（抑制性检查点蛋白）以及人类肝细胞癌（HCC）生物标志物甲胎蛋白（AFP）的免疫组织化学染色。
影像学检查发现40个肿瘤，其中29个被确诊为肝癌，26个被归类为LR-4或5级。其余肿瘤具有良性组织学特征，包括嗜碱性病灶、腺瘤、脂肪变性以及癌前发育异常病灶。LR-4和LR-5级病变对恶性和癌前肿瘤显示出高敏感性（90%）和特异性（100%）。发现肿瘤中的自然杀伤细胞数量相对于正常实质组织低2至5倍，而其他免疫细胞位于肿瘤周边。肿瘤表达AFP但不表达PD-L-L1。
慢性感染WHV的土拨鼠会发生多种肝肿瘤类型，其诊断影像学、病理学和免疫模式与人类相似。这种独特的动物模型可能为新型影像引导和免疫治疗研究的转化和验证提供有价值的工具。
