Sei Yoshitatsu, Feng Jianying, Zhao Xilin, Forbes Joanne, Tang Derek, Nagashima Kunio, Hanson Jeffrey, Quezado Martha M, Hughes Marybeth S, Wank Stephen A
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Electron Microscopy Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland.
Gastroenterology. 2016 Jul;151(1):140-51. doi: 10.1053/j.gastro.2016.03.007. Epub 2016 Mar 18.
BACKGROUND & AIMS: Small intestinal neuroendocrine tumors (SI-NETs) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (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.
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.
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.
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.
小肠神经内分泌肿瘤（SI-NETs）是分泌5-羟色胺的高分化神经内分泌肿瘤，被认为起源于肠嗜铬（EC）细胞。尽管对肿瘤的形成或发展知之甚少，但肠道干细胞（ISC）被认为与SI-NETs的形成有关。我们研究了EC细胞、ISC与SI-NETs之间的关系。
我们分析了2009年1月至2014年12月在美国国立卫生研究院进行的家族性类癌肿瘤自然史研究中纳入的14例家族性SI-NETs患者的空肠-回肠组织标本。通过原位杂交和免疫组化分析不同阶段的冷冻和石蜡包埋肿瘤组织以及分离的隐窝。通过线粒体DNA分析评估肿瘤克隆性。
我们在家族性SI-NETs患者中发现了多灶性异常隐窝内分泌细胞簇（ACECs），其中包含隐窝EC细胞微肿瘤。RNA原位杂交显示ACECs和更晚期的上皮外肿瘤巢中EC细胞和储备干细胞基因TPH1、BMI1、HOPX和LGR5（低表达）的表达。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的+4位置。来自不同肿瘤以及宏观无肿瘤黏膜中的多灶性ACECs的存在表明广泛、独立、多灶性肿瘤发生。线粒体DNA分析证实了ACECs的独立起源。
家族性SI-NETs通过多灶性和多克隆过程起源于EC细胞的一个亚群（表达储备ISC基因的储备EC细胞）。加深我们对这些储备EC细胞在多灶性SI-NETs发生中作用的理解，可能会改善这种难治性疾病的诊断和治疗策略。
