Profiling of Ileal Carcinoids

Nilsson, Ola

doi:10.1159/000343232

Cited by 21 publications

(13 citation statements)

References 243 publications

(135 reference statements)

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“…Since the SI-NETs examined in this study were positive for TPH1, Tac1, NeuroD1 and ChgA and negative for GCG or NTS , the results support the generally accepted proposal that the SI-NET originates from a group of serotonin and substance P producing EC cells 1-4 . Our interest was to estimate if this cell of origin belongs to the ISC gene-expressing subset.…”

Section: Discussionsupporting

confidence: 88%

“…Although rare, SI-NETs are the most common malignant tumors of the small intestine 1 . They display unique biological and genetic profiles that may account for their malignant characteristics and are distinct from other endocrine tumors 1, 2 . Although SI-NETs are thought to originate from enterochromaffin (EC) cells 3, 4 , their precise origin and development remain uncertain.…”

Section: Introductionmentioning

confidence: 99%

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Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

et al. 2016

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Background & Aims Small intestinal neuroendocrine tumors (SI-NET) are serotonin-secreting well-differentiated neuroendocrine tumors believed to originate from enterochromaffin (EC) cells. Intestinal stem cell (ISC) are believed to contribute to formation of SI-NET, 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 (ACEC) that contain crypt EC cell micro-tumors in patients with familial SI-NET. RNA in situ hybridization revealed expression of the EC cell and reserve stem cell genes TPH1, BMI1, HOPX, and LGR5low, in the ACECs and more advanced extra-epithelial tumor nests. This expression pattern resembled that of reserve EC cells that express 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. Conclusion Familial SI-NETs originate from a subset of EC cells (reserve EC cells that express 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.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

et al. 2016

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“…However, none of the MYO5B mutations identified in this study could be found in the online MVID mutation database (http://mvid-central.org, June 25, 2015). Furthermore, MYO5B is positioned at chromosome arm 18q21.1, where chromosomal imbalances have been reported in NETs . Additional mutations in other myosin family members were identified in the current study ( e.g., MYO5A ) and are also reported in other PCC/PGL sequencing studies ( e.g.…”

Section: Discussionsupporting

confidence: 82%

Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes

et al. 2015

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One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p < 0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. In conclusion, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed MYO5B to be recurrently mutated in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis.Pheochromocytomas (PCCs) and paragangliomas (PGLs) are tumors derived from chromaffin cells of the adrenal medulla and extra-adrenal paraganglia. These tumors have a yearly incidence of two to eight per million inhabitants with a peak incidence in the third to fifth decades of life, and occur equally in males and females. 1,2 The proportion of patients that develop malignant disease is estimated to 10% although higher frequencies have been reported, particularly in PGL. 3 The definition of a malignant PCC/PGL is the presence of tumor metastases, 4 and patients with apparently benign

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“…The function of GPR56 in different cancer types was found to differ, with both pro- and anti-tumorigenic properties, so the therapeutic implication of targeting GPR56 in cancer in general awaits careful evaluation. ADGRG4 (GPR112) was reported to serve as a marker for neuroendocrine carcinoma cells [151] and proposed a therapeutic target for treating ileal carcinoids [50]. …”

Section: Tumor Therapy and Adhesion Gpcrsmentioning

confidence: 99%

Adhesion GPCRs in Tumorigenesis

Aust

Zhu

et al. 2016

Handbook of Experimental Pharmacology

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Alterations in the homeostasis of several adhesion GPCRs (aGPCRs) have been observed in cancer. The main cellular functions regulated by aGPCRs are cell adhesion, migration, polarity, and guidance, which are all highly relevant to tumor cell biology. Expression of aGPCRs can be induced, increased, decreased, or silenced in the tumor or in stromal cells of the tumor microenvironment, including fibroblasts and endothelial and/or immune cells. For example, ADGRE5 (CD97) and ADGRG1 (GPR56) show increased expression in many cancers, and initial functional studies suggest that both are relevant for tumor cell migration and invasion. aGPCRs can also impact the regulation of angiogenesis by releasing soluble fragments following the cleavage of their extracellular domain (ECD) at the conserved GPCR-proteolytic site (GPS) or other more distal cleavage sites as typical for the ADGRB (BAI) family. Interrogation of in silico cancer databases suggests alterations in other aGPCR members and provides the impetus for further exploration of their potential role in cancer. Integration of knowledge on the expression, regulation, and function of aGPCRs in tumorigenesis is currently spurring the first preclinical studies to examine the potential of aGPCR or the related pathways as therapeutic targets.

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Profiling of Ileal Carcinoids

Cited by 21 publications

References 243 publications

Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes

Adhesion GPCRs in Tumorigenesis

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