Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Oncogene. 2013 Aug 8;32(32):3664-75. doi: 10.1038/onc.2012.397. Epub 2012 Sep 10.
Epithelial ovarian cancer is an aggressive malignancy, with a low 5-year median survival. Continued improvement on the development of more effective therapies depends in part on the availability of adequate preclinical models for in vivo testing of treatment efficacy. Mucin 1 (MUC1) glycoprotein is a tumor-associated antigen overexpressed in ovarian cancer cells, making it a potential target for immune therapy. To create a preclinical mouse model for MUC1-positive ovarian tumors, we generated triple transgenic (Tg) mice that heterozygously express human MUC1(+/-) as a transgene, and carry the conditional K-rasG12D oncoallele (loxP-Stop-loxP-K-ras(G12D/+)) and the floxed Pten gene (Pten/(loxP/loxP)). Injection of Cre recombinase-encoding adenovirus (AdCre) in the ovarian bursa of triple (MUC1KrasPten) Tg mice triggers ovarian tumors that, in analogy to human ovarian cancer, express strongly elevated MUC1 levels. The tumors metastasize loco-regionally and are accompanied by high serum MUC1, closely mimicking the human disease. Compared with the KrasPten mice with tumors, the MUC1KrasPten mice show increased loco-regional metastasis and augmented accumulation of CD4+Foxp3+ immune-suppressive regulatory T cells. Vaccination of MUC1KrasPten mice with type 1 polarized dendritic cells (DC1) loaded with a MUC1 peptide (DC1-MUC1) can circumvent tumor-mediated immune suppression in the host, activate multiple immune effector genes and effectively prolong survival. Our studies report the first human MUC1-expressing, orthotopic ovarian tumor model, reveal novel MUC1 functions in ovarian cancer biology and demonstrate its suitability as a target for immune-based therapies.
上皮性卵巢癌是一种侵袭性恶性肿瘤，中位 5 年生存率较低。要继续开发更有效的治疗方法，部分取决于是否有足够的临床前模型来进行治疗效果的体内测试。黏蛋白 1（MUC1）糖蛋白是卵巢癌细胞中过表达的肿瘤相关抗原，使其成为免疫治疗的潜在靶点。为了创建 MUC1 阳性卵巢肿瘤的临床前小鼠模型，我们生成了三重转基因（Tg）小鼠，这些小鼠杂合表达人 MUC1(+/-)作为转基因，并携带条件性 K-rasG12D 癌基因（loxP-Stop-loxP-K-ras(G12D/+))和 floxed Pten 基因（Pten/(loxP/loxP))。在三（MUC1KrasPten）Tg 小鼠的卵巢囊中注射携带 Cre 重组酶的腺病毒（AdCre），可引发卵巢肿瘤，这些肿瘤与人类卵巢癌相似，表达强烈升高的 MUC1 水平。肿瘤局部转移，并伴有高血清 MUC1，与人类疾病非常相似。与具有肿瘤的 KrasPten 小鼠相比，MUC1KrasPten 小鼠表现出增加的局部转移和增加的 CD4+Foxp3+免疫抑制调节性 T 细胞的积累。用负载 MUC1 肽的 1 型极化树突细胞（DC1）对 MUC1KrasPten 小鼠进行疫苗接种，可以规避宿主中肿瘤介导的免疫抑制，激活多种免疫效应基因，并有效延长生存时间。我们的研究报告了第一个表达人 MUC1 的、原位卵巢肿瘤模型，揭示了 MUC1 在卵巢癌生物学中的新功能，并证明其适合作为免疫治疗的靶点。
