Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA.
Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA.
Lung Cancer. 2023 Apr;178:157-165. doi: 10.1016/j.lungcan.2023.02.013. Epub 2023 Feb 21.
Lung cancer models in large animals are lacking. Oncopigs are transgenic pigs that carry both KRAS and TP53 Cre-inducible mutations. This study aimed to develop and histologically characterize a swine model of lung cancer that could serve for preclinical studies evaluating locoregional therapies.
In two Oncopigs, an adenoviral vector encoding the Cre-recombinase gene (AdCre) was injected endovascularly through the pulmonary arteries or inferior vena cava. In two other Oncopigs, a lung biopsy was performed and incubated with AdCre, before reinjecting the mixture into the lungs percutaneously. Animals were clinically and biologically (complete blood count, liver enzymes and lipasemia) monitored. Obtained tumors were characterized on computed tomography (CT) and on pathology and immunohistochemistry (IHC).
Neoplastic lung nodules developed following 1 (1/10, 10%) endovascular inoculation, and 2 (2/6, 33%) percutaneous inoculations. All lung tumors were visible at the 1-week CT, and appeared as well-circumscribed solid nodules, with a median longest diameter of 14 mm (range: 5-27 mm). Only one complication occurred: an extravasation of the mixture into the thoracic wall during a percutaneous injection that resulted in a thoracic wall tumor. Pigs remained clinically healthy during the entire follow-up (14-21 days). On histology, tumors consisted of inflammatory undifferentiated neoplasms composed of atypical spindle and epithelioid cells and/or a fibrovascular stroma and abundant mixed leukocytic infiltrate. On IHC, atypical cells diffusely displayed expression of vimentin and some showed expression of CK WSS and CK 8/18. The tumor microenvironment contained abundant IBA1 + macrophages and giant cells, CD3 + T cells, and CD31 + blood vessels.
Tumors induced in the lungs of Oncopigs are fast growing poorly differentiated neoplasms associated with a marked inflammatory reaction that can be easily and safely induced at site specific locations. This large animal model might be suitable for interventional and surgical therapies of lung cancer.
目前缺乏大型动物肺癌模型。Oncopigs 是一种携带 KRAS 和 TP53 Cre 诱导突变的转基因猪。本研究旨在开发并组织学表征一种可用于评估局部区域治疗的肺癌猪模型。
在 2 只 Oncopigs 中，通过肺动脉或下腔静脉内注射携带 Cre 重组酶基因的腺病毒载体（AdCre）。在另外 2 只 Oncopigs 中，进行肺活检并与 AdCre 孵育，然后经皮将混合物重新注入肺部。对动物进行临床和生物学（全血细胞计数、肝酶和脂酶血症）监测。通过计算机断层扫描（CT）、病理学和免疫组织化学（IHC）对获得的肿瘤进行特征描述。
10%（1/10）经血管内接种和 33%（2/6）经皮接种后，形成了肿瘤性肺结节。所有肺部肿瘤在第 1 周的 CT 上均可见，表现为边界清楚的实性结节，最长直径中位数为 14mm（范围：5-27mm）。仅发生 1 例并发症：经皮注射时混合物外渗到胸壁，导致胸壁肿瘤。整个随访期间（14-21 天）猪只均保持临床健康。组织学上，肿瘤由炎症性未分化肿瘤组成，由非典型梭形和上皮样细胞和/或纤维血管基质和丰富的混合白细胞浸润组成。在免疫组化中，非典型细胞弥漫性表达波形蛋白，一些细胞表达 CK WSS 和 CK 8/18。肿瘤微环境中含有丰富的 IBA1+巨噬细胞和巨细胞、CD3+T 细胞和 CD31+血管。
Oncopigs 肺部诱导的肿瘤是快速生长的低分化肿瘤，伴有明显的炎症反应，可在特定部位安全且方便地诱导。这种大型动物模型可能适用于肺癌的介入和手术治疗。
