Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

Sei, Yoshitatsu; Feng, Jianying; Zhao, Xilin; Forbes, Joanne; Tang, Derek M.; Nagashima, Kunio; Hanson, Jeffrey C.; Quezado, Martha; Hughes, Marybeth S.; Wank, Stephen A.

doi:10.1053/j.gastro.2016.03.007

Cited by 25 publications

(32 citation statements)

References 33 publications

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“…The cells we identify with high expression of Bmi1 , EE-restricted TFs, and gut hormones may represent the murine equivalent of crypt cells that give rise to carcinoid tumors. This idea matches with evidence that human carcinoid tumors arise in cells with BMI1 levels modestly higher than in surrounding crypt cells (Sei et al, 2016). …”

Section: Discussionsupporting

confidence: 88%

Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells

et al. 2017

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SUMMARY Replicating Lgr5+ stem cells and quiescent Bmi1+ cells behave as intestinal stem cells (ISCs) in vivo. Disrupting Lgr5+ ISCs triggers epithelial renewal from Bmi1+ cells, from secretory or absorptive progenitors, and from Paneth cell precursors, revealing a high degree of plasticity within intestinal crypts. Here we show that GFP+ cells from Bmi1GFP mice are pre-terminal enteroendocrine cells and identify CD69+CD274+ cells as related goblet cell precursors. Upon loss of native Lgr5+ ISCs, both populations revert towards an Lgr5+ cell identity. While active histone marks are distributed similarly between Lgr5+ ISCs and progenitors of both major lineages, thousands of cis-elements that control expression of lineage-restricted genes are selectively open in secretory cells. This accessibility signature dynamically converts to that of Lgr5+ ISCs during crypt regeneration. Beyond establishing the nature of Bmi1GFP+ cells, these findings reveal how chromatin status underlies intestinal cell diversity and dedifferentiation to restore ISC function and intestinal homeostasis.

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Section: Discussionsupporting

confidence: 88%

Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells

et al. 2017

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“…3B). Previous studies have suggested that SINETs originate from CgA-positive cells in the epithelium at the base of the intestinal crypts (15). We thus also quanti ed the number of CgA-positive cells located speci cally at the bottom of the intestinal crypts (up to and including position + 4), but did again not observe any signi cant difference between the two genotypes (Fig.…”

Section: Heterozygous Inactivation Of Smad4 Is Not Su Cient To Inducementioning

confidence: 76%

SMAD4 Haploinsufficiency in Small Intestinal Neuroendocrine Tumors

Hofving

Elias

Rehammar

et al. 2020

Preprint

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Abstract Background Patients with small intestinal neuroendocrine tumors (SINETs) frequently present with lymph node and liver metastases at the time of diagnosis, but the molecular changes that lead to the progression of these tumors are largely unknown. Sequencing studies have only identified recurrent point mutations in a single gene, CDKN1B, with heterozygous mutations in less than 10% of all tumors. Although SINETs are genetically stable tumors with a low frequency of point mutations and indels, they often harbor recurrent hemizygous copy number alterations (CNAs) yet the functional implications of these CNA are unclear.MethodsUtilizing comparative genomic hybridization (CGH) arrays we analyzed the CNA profile of 131 SINETs from 117 patients. Two tumor suppressor genes and corresponding proteins i.e. SMAD4, and CDKN1B, were further characterized using a tissue microarray (TMA) with 846 SINETs. Immunohistochemistry (IHC) was used to quantify protein expression in TMA samples and this was correlated with chromosome number evaluated with fluorescent in-situ hybridization (FISH). Intestinal tissue from a Smad4+/- mouse model was used to detect entero-endocrine cell hyperplasia with IHC.ResultsAnalyzing the CGH arrays we found loss of chromosome 18q and SMAD4 in 71% of SINETs and that focal loss of chromosome 12 affecting the CDKN1B was present in 9.4% of SINETs. No homozygous loss of chromosome 18 was detected. Hemizygous loss of SMAD4, but not CDKN1B, significantly correlated with reduced protein levels but hemizygous loss of SMAD4 did not induce entero-endocrine cell hyperplasia in the Smad4+/- mouse model. Conclusions Hemizygous loss of chromosome 18q and the SMAD4 gene is the most common genetic event in SINETs and our results suggests that this could influence SMAD4 protein expression. Although SMAD4 haploinsufficiency alone did not induce tumor initiation, loss of chromosome 18 could represent an evolutionary advantage in SINETs explaining the high prevalence of this aberration. Functional consequences of reduced SMAD4 protein levels could hypothetically be a potential mechanism as to why loss of chromosome 18 appears to be clonally selected in SINETs.

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“…The presence of LGR5 ‐positive cell in neuroendocrine neoplasms may suggest that these neoplasms have the same stem cells originating from adenoma and carcinoma in the colorectum. The presence of cells that are positive for both LGR5 and synaptophysin in NEC may be related to acquisition of neuroendocrine features at an early stage of intestinal differentiation . Although there is no evidence that NET G1 and NET G2 are etiologically related to adenoma and adenocarcinoma, one report suggested that LGR5 may be a NET stem cell marker in the small intestine .…”

Section: Discussionmentioning

confidence: 99%

“…The presence of cells that are positive for both LGR5 and synaptophysin in NEC may be related to acquisition of neuroendocrine features at an early stage of intestinal differentiation. 19 Although there is no evidence that NET G1 and NET G2 are etiologically related to adenoma and adenocarcinoma, one report suggested that LGR5 may be a NET stem cell marker in the small intestine. 19 The authors demonstrated the double positive cells for LGR5 and a neuroendocrine marker in NET, suggesting the possibility that LGR5 is stem cell marker in NET.…”

Section: Discussionmentioning

confidence: 99%

“…19 Although there is no evidence that NET G1 and NET G2 are etiologically related to adenoma and adenocarcinoma, one report suggested that LGR5 may be a NET stem cell marker in the small intestine. 19 The authors demonstrated the double positive cells for LGR5 and a neuroendocrine marker in NET, suggesting the possibility that LGR5 is stem cell marker in NET. In our study, the presence of double positive LGR5 and synaptophysin cells Several studies have demonstrated that LGR5 expression correlates with malignancy in some cancers.…”

Section: Discussionmentioning

confidence: 99%

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Leucine‐rich repeat‐containing G‐protein‐coupled receptor 5 expression and clinicopathological features of colorectal neuroendocrine neoplasms

Nakajima

Uehara

Kobayashi

et al. 2018

Pathology International

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LGR5 is expressed in various tumors and has been identified as a putative intestinal stem cell marker. Here we investigated LGR5 expression in colorectal neuroendocrine neoplasms and analyzed the correlation with pathological characteristics. We evaluated the clinicopathological features of 8 neuroendocrine tumor (NET) grade 1 (NET G1), 4 NET Grade 2 (NET G2), and 8 NET Grade 3 (NET G3; also termed neuroendocrine carcinoma, or NEC) cases. We examined LGR5 expression using an RNAscope, a newly developed RNA in situ hybridization technique, with a tissue microarray of the neuroendocrine neoplasm samples. LGR5 staining in individual tumor cells was semi-quantitatively scored using an H-score scale. We also performed a combination of LGR5 RNA in situ hybridization and synaptophysin immunohistochemistry. All cases contained tumor cells with some LGR5-positive dots. For all cases, H-scores showed a positive correlation with nuclear beta-catenin expression. In the NEC group, there was a strong positive correlation between H-score and beta-catenin expression. Our findings suggest that LGR5 may serve as a stem cell marker in NEC, as is the case in colon adenocarcinoma. The positive correlation between H-score and beta-catenin expression suggests that LGR5 expression might be affected by beta-catenin expression in neuroendocrine neoplasms and especially in NEC.

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Polyclonal Crypt Genesis and Development of Familial Small Intestinal Neuroendocrine Tumors

Cited by 25 publications

References 33 publications

Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells

Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells

SMAD4 Haploinsufficiency in Small Intestinal Neuroendocrine Tumors

Leucine‐rich repeat‐containing G‐protein‐coupled receptor 5 expression and clinicopathological features of colorectal neuroendocrine neoplasms

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