Departments of Pathology and Surgery, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.
Clin Cancer Res. 2012 Sep 1;18(17):4612-20. doi: 10.1158/1078-0432.CCR-11-3264. Epub 2012 Jul 3.
In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs.
Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines.
A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway.
Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials.
在小鼠中，失活视网膜母细胞瘤肿瘤抑制途径的遗传变化通常导致胰腺神经内分泌肿瘤（Pan-NET）。相反，在患有这种疾病的人类中，即使在全基因组测序研究中，也很少检测到视网膜母细胞瘤途径基因的突变。在这项研究中，我们更仔细地研究了视网膜母细胞瘤途径在人类 Pan-NET 中的作用。
对 92 名患者的 Pan-NET 肿瘤进行了视网膜母细胞瘤途径标志物的免疫组织化学染色。为了寻找视网膜母细胞瘤途径基因的扩增，对 26 个肿瘤的基因组 DNA 进行了拷贝数分析。最后，测试了一种小分子视网膜母细胞瘤途径激活剂对两种 Pan-NET 细胞系生长的影响。
大多数肿瘤表达大量的 Cdk4 或其伴侣蛋白 cyclin D1。在表达高水平 Cdk4 或 cyclin D1 的肿瘤中，磷酸化 Rb1 的含量较高。在 19%的肿瘤中，Cdk4 或类似激酶基因 Cdk6 的拷贝数增加。在异种移植小鼠模型中，Cdk4/6 抑制剂 PD 0332991 抑制了人 Pan-NET 细胞系 QGP1 的生长，该抑制剂可重新激活视网膜母细胞瘤途径。
大多数 Pan-NET 均表明视网膜母细胞瘤途径失活。Cdk4 和 Cdk6 的基因扩增和过表达表明，Pan-NET 患者可能对正在进行临床试验的 Cdk4/6 抑制剂有强烈反应。
