Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumours

Kawahara, Masaki; Kammori, Makoto; Kanauchi, Hajime; Noguchi, Chiaki; Kuramoto, Shu; Kaminishi, Michio; Endo, Hisako; Takubo, Kaiyo

doi:10.1053/ejso.2001.1229

Cited by 59 publications

(43 citation statements)

References 27 publications

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“…TGFb1 treatment has been shown to decrease E-cadherin levels and cause redistribution of b-catenin in intestinal epithelial cells, 64 suggesting that TGFb1 functions to regulate cell migration and metastasis. Reduced expression of Ecadherin correlates with malignant behavior of GI carcinoids 21 and it appears that TGFb1 pathway alteration of the E-cadherin expression represents a mechanistic component of the malignant evolution.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 In addition, they frequently express c-Myc, 22 a TGFb1 pathway antagonist. This information as well as data that TGFb1 suppresses neuroendocrine cell proliferation 23 has led us to hypothesize that neoplastic EC cells are characterized by down-regulation or loss of the TGFb1-mediated cytostatic program.…”

mentioning

confidence: 99%

“…MTA1 was examined because it is a metastasis factor overexpressed in malignant primary GI carcinoids and their metastases 27 and has been linked to a worse prognosis in patients with EC cellderived appendiceal carcinoids. 28 E-cadherin is of interest because reduced expression correlates with malignant carcinoid behavior, 21 whereas the ERK pathway is relevant because it is active in the majority of GI carcinoids, 29 and may be cross-activated either by TGFb1 30 or by growth factors directly released by TGFb1. 11 It has not been possible to address these mechanistic questions previously because to our knowledge no homogenous human EC cell preparations or cell lines existed until we developed the methodology to isolate and culture normal human small intestinal EC cells.…”

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confidence: 99%

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Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Kidd

Modlin

Pfragner

et al. 2007

Cancer

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Objective To examine whether and to what extent the intracellular trafficking features of HLA–B*2705, which is associated with the development of spondylarthritis (SpA), differ from those of HLA–B*2709 and HLA–B*0702, which are not associated with SpA. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to Renilla luciferase or yellow fluorescent protein. The subcellular distribution of properly folded and unfolded/misfolded HLA–B proteins was examined by flow cytometry and confocal microscopy of cells labeled with ME1 and HC‐10 antibodies, respectively. HLA–B/HLA–B interactions were monitored in endoplasmic reticulum (ER)– and plasma membrane–enriched subcellular fractions, by bioluminescence resonance energy transfer (BRET). Results All 3 HLA–B alleles displayed a similar distribution pattern (properly folded heavy chain at the cell surface, unfolded/misfolded proteins only in the cytoplasm). By means of BRET, we provided evidence that both HLA–B*2705 and HLA–B*2709 formed more oligomers in the ER and the plasma membrane than did HLA–B*0702. The propensity of HLA–B*2705 to form oligomers in the ER was partly attributable to residue Cys67 of the molecule. For all 3 alleles, increased expression of HLA–B proteins was associated with intracytoplasmic accumulation of unfolded/misfolded proteins and intracellular vesicles, probably corresponding to expanded ER–Golgi intermediate compartments, in which these proteins accumulated together with the stress sensor BiP. Conclusion Our results suggest that the difference in disease susceptibility conferred by HLA–B*2705 and HLA–B*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Kidd

Modlin

Pfragner

et al. 2007

Cancer

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“…Reduced expression of E-cadherin by immunohistochemical analyses has been correlated with malignant behavior among patients with gastrointestinal carcinoid tumors. 29 Homozygous loss of function of CTCF gene by tumor-specific rearrangements has been identified in breast carcinomas. 30,31 Interestingly, reported allelic loss of 16q21-qter in metastatic midgut carcinoid tumors but not in primary carcinoid tumors suggests that putative tumor suppressor genes mapped at this locus may be involved in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

et al. 2005

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Carcinoid tumors and pancreatic endocrine tumors are uncommon neuroendocrine neoplasms, and their genetic alterations are not well characterized. These tumors have site-specific differences in neuroendocrine characteristics, clinical course and genetic alterations. We compared clinicopathological features and loss of heterozygosity of chromosomes 11q, 16q and 18, and BRAF gene mutations in 47 patients with neuroendocrine tumors including 16 with pancreatic endocrine tumors, 15 with nonileal carcinoid tumors and 16 with ileal carcinoid tumors. Patients with carcinoid tumors had more frequent history of alcohol consumption compared to patients with pancreatic endocrine tumors (P ¼ 0.02), and patients with ileal carcinoid tumors more frequently had liver metastasis compared to patients with nonileal carcinoid tumors and pancreatic endocrine tumors (P ¼ 0.02). Allelic loss of chromosome 11q was present in 21% of tumors, chromosome 16q in 13%, and chromosome 18 in 30%. These alterations differed with the anatomical subsite of tumor: allelic loss of chromosome 18 was present in 69% of ileal carcinoid tumors, 13% of nonileal carcinoid tumors and 6% of pancreatic endocrine tumors (P ¼ 0.001). In contrast to pancreatic endocrine tumors and nonileal carcinoid tumors, all 11 ileal tumors with loss of chromosome 18 had complete loss of both chromosomal arms. No BRAF mutations were identified. Complete allelic loss of chromosome 18 was associated with smaller tumor size (P ¼ 0.02). Our study indicates that genetic alterations vary by tumor subsite and clinicopathologic features, and ileal carcinoid tumors have distinctive clinicopathologic and genetic profiles.

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“…Indeed, E-cadherin expression is often reduced in SBNETs compared with NSB mucosae and has been correlated with malignant behaviour (Kawahara et al 2002, Li et al 2002. E-cadherin levels are also lower in larger (>2 cm) SBNETs and those with transmural invasion (Li et al 2002).…”

Section: Mir-200 Family Members Are Deregulated In Small Bowel Net Prmentioning

confidence: 99%

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

Miller¹,

Frampton²,

Malczewska³

et al. 2016

Endocrine-Related Cancer

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Novel molecular analytes are needed in small bowel neuroendocrine tumours (SBNETs) to better determine disease aggressiveness and predict treatment response. In this study, we aimed to profile the global miRNome of SBNETs, and identify microRNAs (miRNAs) involved in tumour progression for use as potential biomarkers. Two independent miRNA profiling experiments were performed (n = 90), including primary SBNETs (n = 28), adjacent normal small bowel (NSB; n = 14), matched lymph node (LN) metastases (n = 24), normal LNs (n = 7), normal liver (n = 2) and liver metastases (n = 15). We then evaluated potentially targeted genes by performing integrated computational analyses. We discovered 39 miRNAs significantly deregulated in SBNETs compared with adjacent NSB. The most upregulated (miR-204-5p, miR-7-5p and miR-375) were confirmed by qRT-PCR. Two miRNAs (miR-1 and miR-143-3p) were significantly downregulated in LN and liver metastases compared with primary tumours. Furthermore, we identified upregulated gene targets for miR-1 and miR-143-3p in an existing SBNET dataset, which could contribute to disease progression, and show that these miRNAs directly regulate FOSB and NUAK2 oncogenes. Our study represents the largest global miRNA profiling of SBNETs using matched primary tumour and metastatic samples. We revealed novel miRNAs deregulated during SBNET disease progression, and important miRNA-mRNA interactions. These miRNAs have the potential to act as biomarkers for patient stratification and may also be able to guide treatment decisions. Further experiments to define molecular mechanisms and validate these miRNAs in larger tissue cohorts and in biofluids are now warranted.

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Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumours

Cited by 59 publications

References 27 publications

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor–β1‐mediated regulatory abnormalities including up‐regulation of C‐Myc and MTA1

Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors

MicroRNAs associated with small bowel neuroendocrine tumours and their metastases

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