Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors
Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors
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DOI：
10.1053/j.gastro.2016.03.007
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发表时间：
2016-07-01
期刊：
影响因子：
29.4
通讯作者：
Wank, Stephen A.
中科院分区：
文献类型：
--
作者：
Sei, Yoshitatsu;Feng, Jianying;Wank, Stephen A.
背景与目的：小肠神经内分泌肿瘤（SI-NETs）是一种高度分化的神经内分泌肿瘤，被认为起源于肠嗜铬细胞（EC）。肠干细胞（ISC）被认为有助于SI-NET的形成，尽管对肿瘤的形成或发展知之甚少。我们研究了EC细胞，ISCs和SI-NET之间的关系。方法：我们分析了2009年1月至2014年12月在美国国立卫生研究院参加家族性类癌肿瘤自然史研究的14例家族性SI-NET患者的空回肠组织标本。采用原位杂交和免疫组织化学方法对不同分期的冰冻石蜡包埋肿瘤组织和分离的腺窝进行分析。通过线粒体DNA分析评估肿瘤克隆性。研究结果：我们确定了多灶性异常的含有隐窝的内分泌细胞簇（ACECs），其中含有隐窝EC细胞微肿瘤的家族性SI-NET患者。RNA原位杂交显示，在ACEC和更晚期的上皮外肿瘤巢中，EC细胞和储备干细胞基因TPH 1、BMI 1、HOPX和LGR 5（低）表达。这种表达模式类似于表达储备ISC基因的储备EC细胞;大多数位于正常隐窝中的+4位置。来自单独肿瘤和肉眼可见的无肿瘤粘膜中的多灶性ACEC的存在表明广泛的、独立的、多灶性肿瘤发生。线粒体DNA分析证实了ACEC的独立起源。结论：家族性SI-NET通过多灶性和多克隆过程起源于EC细胞的子集（表达储备ISC基因的储备EC细胞）。增加我们对这些储备EC细胞在多灶性SI-NET发生中的作用的理解，可以改善这种难治性疾病的诊断和治疗策略。
BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from entero-chromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to the formation of SI-NETs, although little is known about tumor formation or development. We investigated the relationship between EC cells, ISCs, and SI-NETs. METHODS: We analyzed jejuno-ileal tissue specimens from 14 patients with familial SI-NETs enrolled in the Natural History of Familial Carcinoid Tumor study at the National Institutes of Health from January 2009 to December 2014. Frozen and paraffin-embedded tumor tissues of different stages and isolated crypts were analyzed by in situ hybridization and immunohistochemistry. Tumor clonality was assessed by analyses of mitochondrial DNA. RESULTS: We identified multifocal aberrant crypt-containing endocrine cell clusters (ACECs) that contain crypt EC cell microtumors in patients with familial SI-NETs. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5(low), in the ACECs and more advanced extraepithelial tumor nests. This expression pattern resembled that of reserve EC cells that express reserve ISC genes; most reside at the +4 position in normal crypts. The presence of multifocal ACECs from separate tumors and in the macroscopic tumor-free mucosa indicated widespread, independent, multifocal tumorigenesis. Analyses of mitochondrial DNA confirmed the independent origin of the ACECs. CONCLUSIONS: Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express reserve ISC genes) via multifocal and polyclonal processes. Increasing our understanding of the role of these reserve EC cells in the genesis of multifocal SI-NETs could improve diagnostic and therapeutic strategies for this otherwise intractable disease.