GROW-School for Oncology & Developmental Biology, Maastricht University, 6229HX Maastricht, The Netherlands.
Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, P. Debyelaan 25, 6229HX Maastricht, The Netherlands.
Int J Mol Sci. 2018 Aug 28;19(9):2547. doi: 10.3390/ijms19092547.
Endometrial cancer (EC) is the most common gynaecological malignancy in Western society and the majority of cases are estrogen dependent. While endocrine drugs proved to be of insufficient therapeutic value in the past, recent clinical research shows promising results by using combinational regimens and pre-clinical studies and identified potential novel endocrine targets. Relevant pre-clinical models can accelerate research in this area. In the present study we describe an orthotopic and estrogen dependent xenograft mouse model of EC. Tumours were induced in one uterine horn of female athymic nude mice using the well-differentiated human endometrial adenocarcinoma Ishikawa cell line-modified to express the luciferase gene for bioluminescence imaging (BLI). BLI and contrast-enhanced computed-tomograph (CE-CT) were used to measure non-invasive tumour growth. Controlled estrogen exposure was achieved by the use of MedRod implants releasing 1.5 μg/d of 17β-estradiol (E2) in ovariectomized mice. Stable E2 serum concentration was demonstrated by LC-MS/MS. Induced tumours were E2 responsive as increased tumour growth was observed in the presence of E2 but not placebo, assessed by BLI, CE-CT, and tumour weight at sacrifice. Metastatic spread was assessed macroscopically by BLI and histology and was seen in the peritoneal cavity, in the lymphovascular space, and in the thoracic cavity. In conclusion, we developed an orthotopic xenograft mouse model of EC that exhibits the most relevant features of human disease, regarding metastatic spread and estrogen dependency. This model offers an easy to manipulate estrogen dosage (by simply adjusting the MedRod implant length), image-guided monitoring of tumour growth, and objectively measurable endpoints (including tumour weight). This is an excellent in vivo tool to further explore endocrine drug regimens and novel endocrine drug targets for EC.
子宫内膜癌（EC）是西方社会最常见的妇科恶性肿瘤，大多数病例依赖于雌激素。尽管过去内分泌药物的治疗价值有限，但最近的临床研究表明，联合治疗方案和临床前研究显示出有希望的结果，并确定了潜在的新的内分泌治疗靶点。相关的临床前模型可以加速该领域的研究。在本研究中，我们描述了一种用于 EC 的同源性和雌激素依赖性异种移植小鼠模型。使用经过改良的具有高分化人子宫内膜腺癌 Ishikawa 细胞系，该细胞系表达荧光素酶基因用于生物发光成像（BLI），在雌性无胸腺裸鼠的一个子宫角中诱导肿瘤。BLI 和对比增强计算机断层扫描（CE-CT）用于测量非侵入性肿瘤生长。通过使用 MedRod 植入物在卵巢切除的小鼠中释放 1.5μg/d 的 17β-雌二醇（E2）来实现受控的雌激素暴露。通过 LC-MS/MS 证明了稳定的 E2 血清浓度。诱导的肿瘤对 E2 有反应，因为在存在 E2 时观察到肿瘤生长增加，但在安慰剂组中没有观察到，通过 BLI、CE-CT 和肿瘤重量在牺牲时进行评估。通过 BLI 和组织学进行宏观评估转移扩散，并且在腹膜腔、淋巴血管空间和胸腔中均可见。总之，我们开发了一种 EC 的同源性异种移植小鼠模型，该模型表现出与人类疾病最相关的特征，包括转移扩散和雌激素依赖性。该模型提供了一种易于操作的雌激素剂量（通过简单地调整 MedRod 植入物的长度）、肿瘤生长的图像引导监测以及可客观测量的终点（包括肿瘤重量）。这是一种极好的体内工具，可以进一步探索 EC 的内分泌药物方案和新型内分泌药物靶点。
