Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.
Identification and characterization of poorly differentiated invasive carcinomas in a mouse model of pancreatic neuroendocrine tumorigenesis.
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DOI：
10.1371/journal.pone.0064472
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Joyce JA
中科院分区：
文献类型：
--
作者：
Hunter KE;Quick ML;Sadanandam A;Hanahan D;Joyce JA
胰腺神经内分泌肿瘤（PanNET）是一种相对罕见但具有临床挑战性的肿瘤类型。特别是，高级别、低分化的PanNET具有最差的患者预后，并且对疾病的潜在机制知之甚少。在这项研究中，我们已经确定并表征了RIP 1-Tag 2小鼠模型中以前未描述的一类低分化PanNET。我们发现，虽然RIP 1-Tag 2模型中的大多数肿瘤是分化良好的胰岛素瘤，但一部分肿瘤已经失去了多种β细胞分化标志物，并且具有高度侵袭性，因此我们将其称为低分化侵袭性癌（PDIC）。此外，我们发现这些肿瘤表现出高有丝分裂指数，类似于人类患者中的低分化（PD）-PanNET。有趣的是，我们通过组织学分析鉴定了Id 1的表达，Id 1是DNA结合基因的抑制剂，也是分化的调节剂，特别是在PDIC肿瘤细胞中。在这种小鼠模型中鉴定PDIC为研究PD-PanNET的病理学和分子特征提供了独特的机会。
Pancreatic neuroendocrine tumors (PanNETs) are a relatively rare but clinically challenging tumor type. In particular, high grade, poorly-differentiated PanNETs have the worst patient prognosis, and the underlying mechanisms of disease are poorly understood. In this study we have identified and characterized a previously undescribed class of poorly differentiated PanNETs in the RIP1-Tag2 mouse model. We found that while the majority of tumors in the RIP1-Tag2 model are well-differentiated insulinomas, a subset of tumors had lost multiple markers of beta-cell differentiation and were highly invasive, leading us to term them poorly differentiated invasive carcinomas (PDICs). In addition, we found that these tumors exhibited a high mitotic index, resembling poorly differentiated (PD)-PanNETs in human patients. Interestingly, we identified expression of Id1, an inhibitor of DNA binding gene, and a regulator of differentiation, specifically in PDIC tumor cells by histological analysis. The identification of PDICs in this mouse model provides a unique opportunity to study the pathology and molecular characteristics of PD-PanNETs.
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