The ETS oncogene family transcription factor FEV identifies serotonin-producing cells in normal and neoplastic small intestine

• Published in: Endocrine-related cancer Vol. 17; no. 1; pp. 283 - 291
• Main Authors: Wang, Yu-cheng, Zuraek, Marlene B, Kosaka, Yasuhiro, Ota, Yasuharu, German, Michael S, Deneris, Evan S, Bergsland, Emily K, Donner, David B, Warren, Robert S, Nakakura, Eric K
• Format: Journal Article
• Language: English
• Published: England Society for Endocrinology 01-03-2010; BioScientifica
• Subjects: Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Carcinoid Tumor - genetics; Carcinoid Tumor - metabolism; Carcinoid Tumor - pathology; Case-Control Studies; Cell Separation - methods; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Enteroendocrine Cells - cytology; Enteroendocrine Cells - metabolism; Enteroendocrine Cells - pathology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Intestinal Neoplasms - genetics; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestine, Small - cytology; Intestine, Small - metabolism; Intestine, Small - pathology; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Liver Neoplasms - secondary; Mice; Mice, Transgenic; Neuroendocrine Tumors - genetics; Neuroendocrine Tumors - metabolism; Neuroendocrine Tumors - pathology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nuclear Proteins - physiology; Regular papers; Serotonin - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism
• DOI: 10.1677/ERC-09-0243
• EISSN: 1479-6821
• ISSN: 1351-0088

Neuroendocrine (NE) or carcinoid tumors of the small intestine (SI) frequently metastasize and produce the hormone serotonin, causing significant morbidity and mortality. A member of the ETS oncogene family of transcription factors, Fev, acts with the homeodomain transcription factor Nkx2.2 in the development of serotonin neurons in mice. In this study, we investigated the role of Fev in normal and neoplastic SI. In NE tumors (NETs) of the SI, serotonin stimulates tumor growth and causes debilitating symptoms, such as diarrhea, flushing, wheezing, and right-sided valvular heart disease (i.e. carcinoid syndrome). Compared with those in the matched normal human SI, FEV expression levels were significantly elevated in primary NETs (20-fold, P<0.0001), lymph node metastases (35-fold, P=0.004), and NET liver metastases (22-fold, P<0.0001) resected from patients with serotonin excess. Fev is expressed in the wild type but not in Nkx2.2 (−/−) mouse SI, in which cells producing serotonin are absent. Using recombination-based cell lineage tracing, we found that FEV-positive cells give rise to serotonin-producing cells in the SI. In Fev (−/−) mouse SI, we observed no difference in the number of cells producing serotonin or other hormones. We conclude that FEV expression identifies serotonin-producing cells in normal and neoplastic SI and is a novel target for diagnosis of patients with NETs of the SI.