Establishment and Validation of an Orthotopic Metastatic Mouse Model of Colorectal Cancer.

Metastases are largely responsible for cancer deaths in solid tumors due to the lack of effective therapies against disseminated disease, and there is an urgent need to fill this gap. This study demonstrates an orthotopic colorectal cancer (CRC) mouse model system to develop spontaneous metastasis in vivo and compare its reproducibility against human CRC. IGF1R-dependent GEO human CRC cells were used to study metastatic colonization using orthotopic transplantation procedures and demonstrated robust liver metastasis. Cell proliferation assays were performed both in the orthotopic primary colon and liver metastatic tumors, and human CRC patient's specimen and similar patterns in H&E and Ki67 staining were observed between the orthotopically generated primary and liver metastatic tumors and human CRC specimens. Microarray analysis was performed to generate gene signatures, compared with deposited human CRC gene expression data sets, analyzed by Oncomine, and revealed similarity in gene signatures with increased aggressive markers expression associated with CRC in orthotopically generated liver metastasis. Thus, we have developed an orthotopic mouse model that reproduces human CRC metastasis. This model system can be effective in developing new therapeutic strategies against disseminated disease and could be implemented for identifying genes that regulate the development and/or maintenance of established metastasis.

在实体肿瘤中，转移是癌症死亡的主要原因，因为缺乏针对播散性疾病的有效疗法，迫切需要填补这一空白。本研究展示了一种原位结直肠癌（CRC）小鼠模型系统，用于在体内产生自发性转移，并将其与人类CRC的可重复性进行比较。使用依赖胰岛素样生长因子1受体（IGF1R）的GEO人类CRC细胞，通过原位移植程序研究转移定植，并显示出强烈的肝转移。在原位原发结肠和肝转移性肿瘤中都进行了细胞增殖测定，并且在原位产生的原发和肝转移性肿瘤与人类CRC标本之间观察到苏木精 - 伊红（H&E）染色和Ki67染色的相似模式。进行了微阵列分析以生成基因特征，与Oncomine分析的已存人类CRC基因表达数据集进行比较，结果显示在原位产生的肝转移中，基因特征与CRC相关的侵袭性标志物表达增加具有相似性。因此，我们开发了一种可重现人类CRC转移的原位小鼠模型。该模型系统可有效用于开发针对播散性疾病的新治疗策略，并可用于识别调节已建立转移的发展和/或维持的基因。