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13 pages, 1843 KiB

Open AccessArticle

Sarcopenia and Ghrelin System in the Clinical Outcome and Prognosis of Gastroenteropancreatic Neuroendocrine Neoplasms

by Yiraldine Herrera-Martínez, Carlos Alzas Teomiro, Soraya León Idougourram, María José Molina Puertas, Alfonso Calañas Continente, Raquel Serrano Blanch, Justo P. Castaño, María Ángeles Gálvez Moreno, Manuel D. Gahete, Raúl M. Luque and Aura D. Herrera-Martínez

Cancers 2022, 14(1), 111; https://doi.org/10.3390/cancers14010111 - 27 Dec 2021

Cited by 8 | Viewed by 2356

Abstract

Background: Malnutrition and sarcopenia affect clinical outcomes and treatment response in cancer patients. Patients with neuroendocrine neoplasms (NENs) may present with additional symptoms related to tumor localization in the gastrointestinal tract and hormone secretion, increasing the risk and effects of sarcopenia. Aim: To [...] Read more.

Background: Malnutrition and sarcopenia affect clinical outcomes and treatment response in cancer patients. Patients with neuroendocrine neoplasms (NENs) may present with additional symptoms related to tumor localization in the gastrointestinal tract and hormone secretion, increasing the risk and effects of sarcopenia. Aim: To explore the presence of malnutrition and sarcopenia in gastroenteropancreatic (GEP)-NEN patients, their relation to tumor characteristics, patient outcomes, survival and the molecular expression of ghrelin system components in the tumor. Patients and methods: One-hundred-and-four patients were included. Anthropometric, biochemical and CT-scans at diagnosis were evaluated. The expression levels of key ghrelin system components were assessed in 63 tumor samples. Results: Nutritional parameters were similar in GEP-NEN tumors of different origin. Relapsed disease was associated with decreased BMI. Patients who presented with weight loss at diagnosis had significantly lower overall survival (108 (25–302) vs. 263 (79–136) months). Ghrelin O-acyltransferase (GOAT) enzyme expression was higher in these patients. The prevalence of sarcopenia using CT images reached 87.2%. Mortality was observed only in patients with sarcopenia. Muscle evaluation was correlated with biochemical parameters but not with the expression of ghrelin system components. Conclusion: Survival is related to the nutritional status of patients with GEP-NENs and also to the molecular expression of some relevant ghrelin system components. Routine nutritional evaluation should be performed in these patients, in order to prescribe appropriate nutritional support, when necessary, for increasing quality of life and improving clinical outcomes. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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14 pages, 3366 KiB

Open AccessArticle

Neuroendocrine Differentiation in Conventional Colorectal Adenocarcinomas: Incidental Finding or Prognostic Biomarker?

by Björn Konukiewitz, Atsuko Kasajima, Maxime Schmitt, Kristina Schwamborn, Tanja Groll, Felix Schicktanz, Claire Delbridge, Lisa Marie Schütze, Dirk Wilhelm, Corinna Lang, Sebastian Lange, Sebastian Foersch, Paul Jank, Katja Steiger, Alexander von Werder, Carsten Denkert, Wilko Weichert, Günter Klöppel and Moritz Jesinghaus

Cancers 2021, 13(20), 5111; https://doi.org/10.3390/cancers13205111 - 12 Oct 2021

Cited by 9 | Viewed by 3142

Abstract

Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior [...] Read more.

Background: Colorectal mixed adenoneuroendocrine carcinomas (MANECs) are clinically highly aggressive neoplasms. MANECs are composed of variable adenocarcinoma components combined with morphologically distinct neuroendocrine carcinoma components, which are confirmed by synaptophysin immunohistochemistry, the gold standard marker of a neuroendocrine differentiation. However, the biological behavior of adenocarcinomas that express synaptophysin but do not show a typical neuroendocrine morphology remains unclear. Methods: We investigated synaptophysin expression in 1002 conventional colorectal adenocarcinomas and correlated the results with clinicopathological characteristics and patient survival and compared the survival characteristics of synaptophysin expression groups to MANECs. Results: Synaptophysin expression in conventional colorectal adenocarcinomas was associated with a shortened disease-free survival (p = 0.037), but not with overall survival or disease-specific survival (DSS) in univariate analyses and without any survival impact in multivariate analyses. Patients with “true” MANECs, on the other hand, showed a significantly shorter survival than all conventional adenocarcinomas with or without synaptophysin expression in uni- and multivariate analyses (e.g., multivariate DSS: p < 0.001, HR: 5.20). Conclusions: Our study demonstrates that synaptophysin expression in conventional colorectal adenocarcinomas, in contrast to MANECs, is not associated with a significantly poorer clinical outcome when compared to adenocarcinomas without synaptophysin expression. Furthermore, our data suggest that conventional adenocarcinomas with a diffuse synaptophysin expression should not be classified as MANECs, also strongly arguing that synaptophysin testing should be reserved for carcinomas with an H&E morphology suggestive of a neuroendocrine differentiation. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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14 pages, 581 KiB

Open AccessArticle

Multicenter Analysis of Treatment Outcomes for Systemic Therapy in Well Differentiated Grade 3 Neuroendocrine Tumors (NET G3)

by Leonidas Apostolidis, Arianna Dal Buono, Elettra Merola, Henning Jann, Dirk Jäger, Bertram Wiedenmann, Eva Caroline Winkler and Marianne Pavel

Cancers 2021, 13(8), 1936; https://doi.org/10.3390/cancers13081936 - 16 Apr 2021

Cited by 19 | Viewed by 2211

Abstract

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than [...] Read more.

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months; p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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19 pages, 20351 KiB

Open AccessArticle

Immunoprofiling in Neuroendocrine Neoplasms Unveil Immunosuppressive Microenvironment

by Antonia Busse, Liliana H. Mochmann, Christiane Spenke, Ruza Arsenic, Franziska Briest, Korinna Jöhrens, Hedwig Lammert, Bence Sipos, Anja A. Kühl, Ralph Wirtz, Marianne Pavel, Michael Hummel, Daniel Kaemmerer, Richard P. Baum and Patricia Grabowski

Cancers 2020, 12(11), 3448; https://doi.org/10.3390/cancers12113448 - 19 Nov 2020

Cited by 14 | Viewed by 3245

Abstract

Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed [...] Read more.

Checkpoint inhibitors have shown promising results in a variety of tumors; however, in neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), low response rates were reported. We aimed herein to investigate the tumor immune microenvironment in NET/NEC to determine whether checkpoint pathways like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) might play a role in immune escape and whether other escape mechanisms might need to be targeted to enable a functional antitumor response. Forty-eight NET and thirty NEC samples were analyzed by immunohistochemistry (IHC) and mRNA immunoprofiling including digital spatial profiling. Through IHC, both NET/NEC showed stromal, but less intratumoral CD3+ T cell infiltration, although this was significantly higher in NEC compared to NET. Expression of PD1, PD-L1, and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) on immune cells was low or nearly absent. mRNA immunoprofiling revealed low expression of IFNγ inducible genes in NET and NEC without any spatial heterogeneity. However, we observed an increased mRNA expression of chemokines, which attract myeloid cells in NET and NEC, and a high abundance of genes related to immunosuppressive myeloid cells and genes with immunosuppressive functions like CD47 and CD74. In conclusion, NET and NEC lack signs of an activation of the adaptive immune system, but rather show abundance of several immunosuppressive genes that represent potential targets for immunomodulation. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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17 pages, 2352 KiB

Open AccessFeature PaperArticle

LAT-1 and GLUT-1 Carrier Expression and Its Prognostic Value in Gastroenteropancreatic Neuroendocrine Tumors

by Miguel Sampedro-Núñez, Antonio Bouthelier, Ana Serrano-Somavilla, Rebeca Martínez-Hernández, Magdalena Adrados, Elena Martín-Pérez, José Luis Muñoz de Nova, José Manuel Cameselle-Teijeiro, Concepción Blanco-Carrera, José Manuel Cabezas-Agricola, José Ángel Díaz, Rogelio García-Centeno, Julian Aragones and Mónica Marazuela

Cancers 2020, 12(10), 2968; https://doi.org/10.3390/cancers12102968 - 13 Oct 2020

Cited by 10 | Viewed by 2665

Abstract

Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in [...] Read more.

Cancer cells develop mechanisms that increase nutrient uptake, including key nutrient carriers, such as amino acid transporter 1 (LAT-1) and glucose transporter 1 (GLUT-1), regulated by the oxygen-sensing Von Hippel Lindau-hypoxia-inducible factor (VHL-HIF) transcriptional pathway. We aimed to analyze these metabolic players in gastroenteropancreatic neuroendocrine tumors (GEP-NET) and correlate them with tumor malignancy and progression. LAT-1, GLUT-1, and pVHL expression was analyzed in 116 GEP-NETs and 48 peritumoral tissue samples by immunohistochemistry. LAT-1 was stably silenced using specific shRNA in the human NET BON cell line. LAT-1 expression was significantly increased in tumor tissue compared to non-tumor tissue in both gastrointestinal (67% vs. 44%) and pancreatic NETs (54% vs. 31%). Similarly, GLUT-1 was substantially elevated in gastrointestinal (74% vs. 19%) and pancreatic (58% vs. 4%) NETs. In contrast, pVHL expression was decreased (85% vs. 58%) in pancreatic NETs. Tumors with metastases at diagnosis displayed increased LAT-1 and GLUT-1 and decreased pVHL expression (p < 0.001). In accordance with these data, silencing LAT-1 curtailed cell proliferation in BON cells. These findings suggest that specific mechanisms that increase nutrient uptake, such as LAT-1 and GLUT-1, are increased in GEP-NETs, whereas pVHL is decreased. These markers might be related to the proliferation and metastatic capacity of these tumors. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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12 pages, 907 KiB

Open AccessArticle

Classifying Lung Neuroendocrine Neoplasms through MicroRNA Sequence Data Mining

by Justin J. M. Wong, Paula S. Ginter, Kathrin Tyryshkin, Xiaojing Yang, Jina Nanayakkara, Zier Zhou, Thomas Tuschl, Yao-Tseng Chen and Neil Renwick

Cancers 2020, 12(9), 2653; https://doi.org/10.3390/cancers12092653 - 17 Sep 2020

Cited by 11 | Viewed by 2995

Abstract

Lung neuroendocrine neoplasms (NENs) can be challenging to classify due to subtle histologic differences between pathological types. MicroRNAs (miRNAs) are small RNA molecules that are valuable markers in many neoplastic diseases. To evaluate miRNAs as classificatory markers for lung NENs, we generated comprehensive [...] Read more.

Lung neuroendocrine neoplasms (NENs) can be challenging to classify due to subtle histologic differences between pathological types. MicroRNAs (miRNAs) are small RNA molecules that are valuable markers in many neoplastic diseases. To evaluate miRNAs as classificatory markers for lung NENs, we generated comprehensive miRNA expression profiles from 14 typical carcinoid (TC), 15 atypical carcinoid (AC), 11 small cell lung carcinoma (SCLC), and 15 large cell neuroendocrine carcinoma (LCNEC) samples, through barcoded small RNA sequencing. Following sequence annotation and data preprocessing, we randomly assigned these profiles to discovery and validation sets. Through high expression analyses, we found that miR-21 and -375 are abundant in all lung NENs, and that miR-21/miR-375 expression ratios are significantly lower in carcinoids (TC and AC) than in neuroendocrine carcinomas (NECs; SCLC and LCNEC). Subsequently, we ranked and selected miRNAs for use in miRNA-based classification, to discriminate carcinoids from NECs. Using miR-18a and -155 expression, our classifier discriminated these groups in discovery and validation sets, with 93% and 100% accuracy. We also identified miR-17, -103, and -127, and miR-301a, -106b, and -25, as candidate markers for discriminating TC from AC, and SCLC from LCNEC, respectively. However, these promising findings require external validation due to sample size. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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Graphical abstract

21 pages, 1900 KiB

Open AccessArticle

Circulating miRNA Increases the Diagnostic Accuracy of Chromogranin A in Metastatic Pancreatic Neuroendocrine Tumors

by Annamária Kövesdi, Petra Anna Kurucz, Gábor Nyírő, Ottó Darvasi, Attila Patócs and Henriett Butz

Cancers 2020, 12(9), 2488; https://doi.org/10.3390/cancers12092488 - 02 Sep 2020

Cited by 7 | Viewed by 2050

Abstract

Chromogranin A (CgA) is the most widely accepted biomarker for neuroendocrine tumors (NET) but its diagnostic accuracy is dependent on tumor type and the use of proton-pump inhibitors (PPI). We investigated the diagnostic value of circulating miRNAs along with CgA in pancreatic neuroendocrine [...] Read more.

Chromogranin A (CgA) is the most widely accepted biomarker for neuroendocrine tumors (NET) but its diagnostic accuracy is dependent on tumor type and the use of proton-pump inhibitors (PPI). We investigated the diagnostic value of circulating miRNAs along with CgA in pancreatic neuroendocrine tumors (pNET). 74 serum samples from patients with pNET (n = 25, nonfunctioning), pheochromocytoma/paraganglioma (PPGL, n = 20), healthy individuals with normal CgA (n = 29) including 10 samples from 5 healthy individuals with and without current PPI treatment were collected. MiRNA expression profiles were determined using next-generation sequencing, followed by validation with individual TaqMan assays. A global downregulation of miRNAs was observed in patients with NET compared to controls. MiRNA expression of 33 miRNAs was able to discriminate tumor samples from controls. No miRNA alone could be considered as an applicable biomarker for pNET or PPGL. However, using a logistic model, the combination of a set of miRNAs increased the discriminatory role of CgA irrespective of PPI treatment. In pNET patients with normal CgA level our regression model yielded high (89.4%) diagnostic accuracy (AUC: 0.904, sensitivity: 66.6%, specificity: 96.5%). A set of miRNAs increased the diagnostic utility of CgA in pNET even in patients with low CgA. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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15 pages, 6663 KiB

Open AccessArticle

Usefulness of FDG-PET/CT-Based Radiomics for the Characterization and Genetic Orientation of Pheochromocytomas Before Surgery

by Catherine Ansquer, Delphine Drui, Eric Mirallié, Karine Renaudin-Autain, Antoine Denis, Anne-Paule Gimenez-Roqueplo, Christophe Leux, Frederique Toulgoat, Françoise Kraeber-Bodéré and Thomas Carlier

Cancers 2020, 12(9), 2424; https://doi.org/10.3390/cancers12092424 - 26 Aug 2020

Cited by 14 | Viewed by 31249

Abstract

Purpose: To assess the potential added value of FDG-PET/CT radiomics for the characterization of pheochromocytomas (PHEO) and their genetic orientation prior to surgery and genetic testing. Methods: This retrospective monocentric study, included 49 patients (52 tumors) that underwent both FDG-PET/CT and MIBG scan [...] Read more.

Purpose: To assess the potential added value of FDG-PET/CT radiomics for the characterization of pheochromocytomas (PHEO) and their genetic orientation prior to surgery and genetic testing. Methods: This retrospective monocentric study, included 49 patients (52 tumors) that underwent both FDG-PET/CT and MIBG scan before surgery. A germline mutation was secondarily identified in 13 patients in one of the genes related to Cluster 1 (n = 4) or Cluster 2 (n = 9). No mutation was identified in 32 patients and 4 did not have genetic testing. Correlation between several PET-based biomarkers, including SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and textural features, and biochemical and genetic features were analyzed. Results: Sensitivity of FDG-PET/CT alone was 92%, and 98% when combined to MIBG. The SUVmax was significantly higher for mutated tumors classified in Cluster 1 than in Cluster 2 (p = 0.002) or for tumors with no identified mutations (p = 0.04). MTV and TLG of the tumors with the most intense uptake discriminated mutated Cluster 2 from sporadic tumors, but not from Cluster 1 tumors. Textural features combined with MTV led to better differentiation between sporadic and mutated tumors (p < 0.05). Conclusion: FDG-PET/CT is useful for preoperative characterization of PHEO, and when combined with radiomics biomarkers, provides evidences for a genetic predisposition. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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15 pages, 4157 KiB

Open AccessArticle

Effect of Octreotide Long-Acting Release on Tregs and MDSC Cells in Neuroendocrine Tumour Patients: A Pivotal Prospective Study

by Claudia von Arx, Giuseppina Rea, Maria Napolitano, Alessandro Ottaiano, Fabiana Tatangelo, Francesco Izzo, Antonella Petrillo, Ottavia Clemente, Antonella Di Sarno, Gerardo Botti, Stefania Scala and Salvatore Tafuto

Cancers 2020, 12(9), 2422; https://doi.org/10.3390/cancers12092422 - 26 Aug 2020

Cited by 6 | Viewed by 2629

Abstract

Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, [...] Read more.

Octreotide long-acting repeatable (LAR) is largely used to treat functional and/or metastatic neuroendocrine neoplasms (NENs). Its effect in controlling carcinoid syndrome and partially reduce tumour burden is attributable to the ability of octreotide to bind somatostatin receptors (SSTRs) on the tumour and metastasis, regulating growth hormone secretion and cell growth. Notably, SSTRs are also expressed, at different levels, on Tregs. Tregs, together with myeloid-derived suppressor cells (MDSCs), are key components in the anti-tumour immunoregulation. This is the first prospective study aimed to explore the impact of Octreotide (OCT) LAR on the immune system, with a particular focus on Tregs and MDSC cells. Here, we show that circulating Tregs are elevated in NENs patients compared to healthy donors and that treatment with OCT LAR significantly decrease the level of total Tregs and of the three functional Tregs populations: nTregs, eTregs and non-Tregs. Furthermore, OCT LAR treatment induces a functional impairment of the remaining circulating Tregs, significantly decreasing the expression of PD1, CTLA4 and ENTPD1. A trend in circulating MDSC cells is reported in patients treated with OCT LAR. The results reported here suggest that the effect of OCT LAR on Tregs could tip the balance of the patients’ immune-system towards a durable anti-tumour immunosurveillance with consequent long-term control of the NENs disease. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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13 pages, 1294 KiB

Open AccessArticle

Liver Tumor Burden in Pancreatic Neuroendocrine Tumors: CT Features and Texture Analysis in the Prediction of Tumor Grade and ¹⁸F-FDG Uptake

by Alessandro Beleù, Giulio Rizzo, Riccardo De Robertis, Alessandro Drudi, Gregorio Aluffi, Chiara Longo, Alessandro Sarno, Sara Cingarlini, Paola Capelli, Luca Landoni, Aldo Scarpa, Claudio Bassi and Mirko D’Onofrio

Cancers 2020, 12(6), 1486; https://doi.org/10.3390/cancers12061486 - 07 Jun 2020

Cited by 7 | Viewed by 3517

Abstract

Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms that often present with liver metastases. Histological characteristics, metabolic behavior, and liver tumor burden (LTB) are important prognostic factors. In this study, the usefulness of texture analysis of liver metastases in evaluating the [...] Read more.

Pancreatic neuroendocrine tumors (p-NETs) are a rare group of neoplasms that often present with liver metastases. Histological characteristics, metabolic behavior, and liver tumor burden (LTB) are important prognostic factors. In this study, the usefulness of texture analysis of liver metastases in evaluating the biological aggressiveness of p-NETs was assessed. Fifty-six patients with liver metastases from p-NET were retrospectively enrolled. Qualitative and quantitative CT features of LTB were evaluated. Histogram-derived parameters of liver metastases were calculated and correlated with the tumor grade (G) and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) standardized uptake value (SUV). Arterial relative enhancement was inversely related with G (−0.37, p = 0.006). Different metastatic spread patterns of LTB were not associated with histological grade. Arterial_entropy was significantly correlated to G (−0.368, p = 0.038) and to Ki67 percentage (−0.421, p = 0.018). The ROC curve for the Arterial_entropy reported an area under the curve (AUC) of 0.736 (95% confidence interval 0.545–0.928, p = 0.035) in the identification of G1–2 tumors. Arterial_uniformity values were correlated to G (0.346, p = 0.005) and Ki67 levels (0.383, p = 0.033). Arterial_entropy values were directly correlated with the SUV (0.449, p = 0.047) which was inversely correlated with Arterial_uniformity (−0.499, p = 0.025). Skewness and kurtosis reported no significant correlations. In conclusion, histogram-derived parameters may predict adverse histological features and metabolic behavior of p-NET liver metastases. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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20 pages, 3707 KiB

Open AccessArticle

PDX1 DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis

by Gitta Boons, Timon Vandamme, Joe Ibrahim, Geert Roeyen, Ann Driessen, Dieter Peeters, Ben Lawrence, Cristin Print, Marc Peeters, Guy Van Camp and Ken Op de Beeck

Cancers 2020, 12(6), 1461; https://doi.org/10.3390/cancers12061461 - 04 Jun 2020

Cited by 19 | Viewed by 4186

Abstract

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, [...] Read more.

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the PDX1 region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the PDX1 methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051–0.95], p = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the PDX1 methylation status for the subtyping of PNENs and its prognostic importance. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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11 pages, 1249 KiB

Open AccessArticle

A 30-Year Long-Term Experience in Appendix Neuroendocrine Neoplasms—Granting a Positive Outcome

by João Vinagre, Jorge Pinheiro, Olga Martinho, Rui Manuel Reis, John Preto, Paula Soares and José Manuel Lopes

Cancers 2020, 12(6), 1357; https://doi.org/10.3390/cancers12061357 - 26 May 2020

Cited by 6 | Viewed by 2932

Abstract

Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to [...] Read more.

Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to cell cycle proliferation and/or senescence-type, apoptotic, and metastatic potential. Appendix NENs were detected in 74 patients, with 0.47% of incidence per appendectomy. The median age of the patients was 21.5 years, with two age peaks of incidence at 17.0 and 55.2 years. The median tumors size was 5.8 mm, and most were smaller than 10 mm. Lymphovascular and perineural invasion, as well as necrosis, was associated with larger tumor size. G1 tumors composed 96.0% of the cohort. The presence of moderate/strong p16 and the absent/low Bcl-2 expression was frequently observed and associated with a smaller size. This study represents one of the largest cohorts and with a long follow-up. For tumors smaller than 10 mm appendicectomy was sufficient as a curative procedure, as revealed by the good outcome. This series presented a 100% disease-free survival. The indolent phenotype of appendix NENs is supported by the expression of markers that point towards a strong inhibition of cell replication and growth inhibition. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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12 pages, 1644 KiB

Open AccessArticle

Gonadotroph Tumors Show Subtype Differences that Might Have Implications for Therapy

by Mirela Diana Ilie, Alexandre Vasiljevic, Camille Louvet, Emmanuel Jouanneau and Gérald Raverot

Cancers 2020, 12(4), 1012; https://doi.org/10.3390/cancers12041012 - 20 Apr 2020

Cited by 16 | Viewed by 2537

Abstract

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed [...] Read more.

Gonadotroph tumors, although frequent, are poorly studied and understood, being usually included in the larger nonfunctioning pituitary neuroendocrine tumors (PitNETs) group. Moreover, in comparison to the other types of PitNETs, no established medical treatment is currently available for gonadotroph tumors. Here, we performed a retrospective study and analyzed the clinicopathological characteristics of 98 gonadotroph tumors operated in a single large pituitary center. Although being larger in men (p = 0.01), the aggressiveness of gonadotroph tumors did not appear to be sex-related. LH tumors were rare (4/98) and exclusively encountered in men. Somatostatin receptor type 5 (SST5) was absent in all analyzed tumors. The immunoreactive score (IRS) of somatostatin receptor type 2 (SST2) and of estrogen receptor alpha (ERα) was associated with the histological subtype (p = 0.01 and p = 0.02). IRS ERα correlated moderately with IRS SST2 in all (rho = 0.44, adjusted p-value = 0.0001) and in male (rho = 0.51, adjusted p-value = 0.0002) patients, and with follicle-stimulating hormone (FSH) percentage in all (rho = 0.40, adjusted p-value = 0.0005) and in female (rho = 0.58, adjusted p-value = 0.004) patients. In conclusion, gonadotroph tumors exhibit histological characteristics pinpointing the existence of several subtypes. Their heterogeneity warrants further investigations and may have to be taken into account when studying these tumors and investigating treatment options. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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15 pages, 7526 KiB

Open AccessArticle

The Calcium-Sensing Receptor is A Marker and Potential Driver of Neuroendocrine Differentiation in Prostate Cancer

by Fanny Bery, Mathilde Cancel, Aurélie Chantôme, Roseline Guibon, Franck Bruyère, François Rozet, Karine Mahéo and Gaëlle Fromont

Cancers 2020, 12(4), 860; https://doi.org/10.3390/cancers12040860 - 02 Apr 2020

Cited by 15 | Viewed by 2630

Abstract

The mechanisms underlying neuroendocrine (NE) differentiation in prostate cancer (PCa) remain mostly uncharacterized. Since a deregulated calcium homeostasis has been reported in neuroendocrine prostate cancer (NEPC), we explored herein the link between NE differentiation and the calcium-sensing receptor (CaSR). CaSR expression was evaluated [...] Read more.

The mechanisms underlying neuroendocrine (NE) differentiation in prostate cancer (PCa) remain mostly uncharacterized. Since a deregulated calcium homeostasis has been reported in neuroendocrine prostate cancer (NEPC), we explored herein the link between NE differentiation and the calcium-sensing receptor (CaSR). CaSR expression was evaluated by immunohistochemistry—together with NE markers—on tissue microarrays containing samples of normal prostate, localized PCa, metastatic castration resistant PCa (MCRPC) and NEPC. In prostate tissues, we observed a strong association between CaSR and chromogranin expression. Both markers were strongly expressed in all cases of NEPC and co-expression was confirmed by double immunostaining. In MCRPC, the expression of CaSR was significantly associated with shorter overall survival. The involvement of CaSR in NE differentiation was evaluated in PCa cell lines. Inhibition of CaSR led to decrease the expression of neuronal (NSE, βtubulinIII) and NE (chromogranin, synaptophysin) markers in the NE PCa cell line NCI-H660. A decrease of neuronal and NE markers was also observed in siCaSR-transfected PC3 and 22RV1 cells, respectively, whereas CaSR activation increased both NSE and synaptophysin expression in PC3 cells. These results strongly suggest that CaSR is a marker and a driver of NE differentiation in PCa and emphasize the potential of CaSR directed therapy for NEPC patients. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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18 pages, 1894 KiB

Open AccessArticle

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1

by Kim B. Luley, Shauni B. Biedermann, Axel Künstner, Hauke Busch, Sören Franzenburg, Jörg Schrader, Patricia Grabowski, Ulrich F. Wellner, Tobias Keck, Georg Brabant, Sebastian M. Schmid, Hendrik Lehnert and Hendrik Ungefroren

Cancers 2020, 12(3), 691; https://doi.org/10.3390/cancers12030691 - 14 Mar 2020

Cited by 29 | Viewed by 5910

Abstract

Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin [...] Read more.

Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17–92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial–mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro. Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the “islet/insulinoma tumors” (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as “metastasis-like/primary” (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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20 pages, 9997 KiB

Open AccessArticle

Inhibition of Wnt/β-Catenin Signaling in Neuroendocrine Tumors In Vitro: Antitumoral Effects

by Xi-Feng Jin, Gerald Spöttl, Julian Maurer, Svenja Nölting and Christoph Josef Auernhammer

Cancers 2020, 12(2), 345; https://doi.org/10.3390/cancers12020345 - 04 Feb 2020

Cited by 28 | Viewed by 3775

Abstract

Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of [...] Read more.

Background and aims: Inhibition of Wnt/β-catenin signaling by specific inhibitors is currently being investigated as an antitumoral strategy for various cancers. The role of Wnt/β-catenin signaling in neuroendocrine tumors still needs to be further investigated. Methods: This study investigated the antitumor activity of the porcupine (PORCN) inhibitor WNT974 and the β-catenin inhibitor PRI-724 in human neuroendocrine tumor (NET) cell lines BON1, QGP-1, and NCI-H727 in vitro. NET cells were treated with WNT974, PRI-724, or small interfering ribonucleic acids against β-catenin, and subsequent analyses included cell viability assays, flow cytometric cell cycle analysis, caspase3/7 assays and Western blot analysis. Results: Treatment of NET cells with WNT974 significantly reduced NET cell viability in a dose- and time-dependent manner by inducing NET cell cycle arrest at the G1 and G2/M phases without inducing apoptosis. WNT974 primarily blocked Wnt/β-catenin signaling by the dose- and time-dependent downregulation of low-density lipoprotein receptor-related protein 6 (LRP6) phosphorylation and non-phosphorylated β-catenin and total β-catenin, as well as the genes targeting the latter (c-Myc and cyclinD1). Furthermore, the WNT974-induced reduction of NET cell viability occurred through the inhibition of GSK-3-dependent or independent signaling (including pAKT/mTOR, pEGFR and pIGFR signaling). Similarly, treatment of NET cells with the β-catenin inhibitor PRI-724 caused significant growth inhibition, while the knockdown of β-catenin expression by siRNA reduced NET tumor cell viability of BON1 cells but not of NCI-H727 cells. Conclusions: The PORCN inhibitor WNT974 possesses antitumor properties in NET cell lines by inhibiting Wnt and related signaling. In addition, the β-catenin inhibitor PRI-724 possesses antitumor properties in NET cell lines. Future studies are needed to determine the role of Wnt/β-catenin signaling in NET as a potential therapeutic target. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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Review

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18 pages, 1333 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Genetic Drivers of Ileal Neuroendocrine Tumors

by Darren R. Carpizo and Chris R. Harris

Cancers 2021, 13(20), 5070; https://doi.org/10.3390/cancers13205070 - 10 Oct 2021

Cited by 5 | Viewed by 3021

Abstract

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing [...] Read more.

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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16 pages, 1678 KiB

Open AccessReview

Neuroendocrine Lung Cancer Mouse Models: An Overview

by Corina Lorz, Marta Oteo and Mirentxu Santos

Cancers 2021, 13(1), 14; https://doi.org/10.3390/cancers13010014 - 22 Dec 2020

Cited by 4 | Viewed by 3003

Abstract

Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal [...] Read more.

Neuroendocrine lung tumors comprise a range of malignancies that extend from benign tumorlets to the most prevalent and aggressive Small Cell Lung Carcinoma (SCLC). They also include low-grade Typical Carcinoids (TC), intermediate-grade Atypical Carcinoids (AC) and high-grade Large Cell Neuroendocrine Carcinoma (LCNEC). Optimal treatment options have not been adequately established: surgical resection when possible is the choice for AC and TC, and for SCLC chemotherapy and very recently, immune checkpoint inhibitors. Some mouse models have been generated based on the molecular alterations identified in genomic analyses of human tumors. With the exception of SCLC, there is a limited availability of (preclinical) models making their development an unmet need for the understanding of the molecular mechanisms underlying these diseases. For SCLC, these models are crucial for translational research and novel drug testing, given the paucity of human material from surgery. The lack of early detection systems for lung cancer point them out as suitable frameworks for the identification of biomarkers at the initial stages of tumor development and for testing molecular imaging methods based on somatostatin receptors. Here, we review the relevant models reported to date, their impact on the understanding of the biology of the tumor subtypes and their relationships, as well as the effect of the analyses of the genetic landscape of the human tumors and molecular imaging tools in their development. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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28 pages, 957 KiB

Open AccessReview

Landscape and Future Perspectives of Immunotherapy in Neuroendocrine Neoplasia

by Ilaria Maggio, Lisa Manuzzi, Giuseppe Lamberti, Angela Dalia Ricci, Nastassja Tober and Davide Campana

Cancers 2020, 12(4), 832; https://doi.org/10.3390/cancers12040832 - 30 Mar 2020

Cited by 29 | Viewed by 4993

Abstract

Background: Neuroendocrine neoplasms are rare entities consisting of a heterogeneous group of tumors that can originate from neuroendocrine cells present in the whole body. Their different behavior, metastatic potential, and prognosis are highly variable, depending on site of origin, grade of differentiation, and [...] Read more.

Background: Neuroendocrine neoplasms are rare entities consisting of a heterogeneous group of tumors that can originate from neuroendocrine cells present in the whole body. Their different behavior, metastatic potential, and prognosis are highly variable, depending on site of origin, grade of differentiation, and proliferative index. The aim of our work is to summarize the current knowledge of immunotherapy in different neuroendocrine neoplasms and its implication in clinical practice. Results: Several studies evaluated the efficacy and safety of immunotherapy in neuroendocrine neoplasms, in any setting of treatment, alone or in combination. Studies led to approval in neuroendocrine neoplasia of the lung, in combination with chemotherapy as first-line treatment or as a single-agent in a third-line setting, and Merkel cell carcinoma as a single agent. Results in other settings have been disappointing so far. Conclusions: Immunotherapy seems a valid treatment option for high grade, poorly differentiated neoplasms. Future trials should explore the combination of immunotherapy with other agents, such as anti-angiogenic or other immunotherapy agents, in order to evaluate potential efficacy in low and intermediate grades, well differentiated tumors. Full article

(This article belongs to the Special Issue Advances in Neuroendocrine Neoplasms Research)

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