MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma
MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma
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DOI：
10.4049/jimmunol.181.5.3116
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发表时间：
2008-09-01
影响因子：
4.4
通讯作者：
Mukherjee, Pinku
中科院分区：
文献类型：
--
作者：
Tinder, Teresa L.;Subramani, Durai B.;Mukherjee, Pinku
MUC1是一种膜连接的粘蛋白糖蛋白，在80%的人胰腺导管癌中过度表达并异常糖基化。然而，MUC1在胰腺癌中的作用一直难以捉摸，部分原因是缺乏适当的模型。我们报道了一种将人MUC1表达为自身分子的新型小鼠模型(PDA.MUC1小鼠)的特征。胰腺肿瘤发生在具有免疫能力的宿主体内的适当的MUC1耐受背景下。在PDA中观察到胰腺上皮内癌前病变和发展为腺癌的显著增强，可能是由于增殖增加所致。与缺乏MUC1的PDA小鼠相比，MUC1小鼠的肿瘤表达更高水平的环氧合酶-2和IDO，特别是在肿瘤发展的早期阶段。促炎环境的增加与胰腺肿瘤和肿瘤引流淋巴结中调节性T细胞和髓系抑制细胞比例的增加有关。数据显示，在胰腺癌进展过程中，MUC1介导的机制促进了疾病的发生和发展，进而调节免疫反应。因此，小鼠模型非常适合测试针对胰腺癌的新的化学预防和治疗策略。
MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in > 80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.