Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

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• 作者：Yoshitatsu Sei¹ ; Jianying Feng¹ ; Xilin Zhao¹ ; Joanne Forbes¹ ; Derek Tang¹ ; Kunio Nagashima² ; Jeffrey Hanson³ ; Martha M. Quezado³ ; Marybeth S. Hughes⁴ ; Stephen A. Wank¹ ; ^{stevew@mail.nih.gov" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Small Intestine ; Cancer ; Malignancy ; Gene Expression
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：151
• 期：1
• 页码：140-151
• 全文大小：5376 K

文摘

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.

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.