Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1
Heterozygous Men1 mutant mice develop a range of endocrine tumors mimicking multiple endocrine neoplasia type 1
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DOI：
10.1210/me.2003-0154
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发表时间：
2003-09-01
影响因子：
--
通讯作者：
Zhang, CX
中科院分区：
文献类型：
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作者：
Bertolino, P;Tong, WM;Zhang, CX
多发性内分泌瘤1型（MEN1）是一种遗传性综合征，其特征是患者发生甲状旁腺、胰腺和垂体前叶的多发性内分泌肿瘤。为了研究与MEN1综合征相关的肿瘤发生，我们使用基因靶向方法产生了Men1敲除小鼠。杂合Men1突变小鼠发生与MEN1患者相同范围的主要内分泌肿瘤，影响甲状旁腺，胰岛，垂体和肾上腺以及甲状腺，并表现出具有转移潜力的多阶段肿瘤进展。特别是，胰腺外胃泌素瘤，胰腺胰高血糖素瘤，和混合性胰岛分泌肿瘤进行了观察。此外，在杂合子Men1突变小鼠中，内分泌来源的性腺肿瘤（即Leydig细胞肿瘤）和卵巢性索间质细胞肿瘤的发病率较高。在这些小鼠中还观察到激素紊乱，如异常PTH和胰岛素水平。这些肿瘤与野生型Men1等位基因的杂合性丢失相关，表明menin参与抑制这些内分泌肿瘤的发展。所有这些特征都让人联想到人类的MEN1症状，并建立了杂合Men1突变小鼠作为这种疾病的合适模型。
Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by the occurrence of multiple endocrine tumors of the parathyroid, pancreas, and anterior pituitary in patients. To study tumorigenesis related to the MEN1 syndrome, we have generated Men1 knockout mice using the gene targeting approach. Heterozygous Men1 mutant mice developed the same range of major endocrine tumors as is seen in MEN1 patients, affecting the parathyroid, pancreatic islets, pituitary and adrenal glands, as well as the thyroid, and exhibiting multistage tumor progression with metastatic potential. In particular, extrapancreatic gastrinoma, pancreatic glucagonoma, and mixed hormone-producing tumors in islets were observed. In addition, there was a high incidence of gonadal tumors of endocrine origin, i.e. Leydig cell tumors, and ovary sex-cord stromal cell tumors in heterozygous Men1 mutant mice. Hormonal disturbance, such as abnormal PTH and insulin levels, was also observed in these mice. These tumors were associated with loss of heterozygosity of the wild-type Men1 allele, suggesting that menin is involved in suppressing the development of these endocrine tumors. All of these features are reminiscent of MEN1 symptoms in humans and establish heterozygous Men1 mutant mice as a suitable model for this disease.