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Federico Gatto and Leo J Hofland

Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D2 receptor (D2) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D2 as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D2 pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.

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Thomas Cuny, Wouter de Herder, Anne Barlier, and Leo J Hofland

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a group of heterogeneous tumors whose incidence increased over the past few years. Around half of patients already present with metastatic disease at the initial diagnosis. Despite extensive efforts, cytotoxic and targeted therapies have provided only limited efficacy for patients with metastatic GEP-NETs, mainly due to the development of a certain state of resistance. One factor contributing to both the failure of systemic therapies and the emergence of an aggressive tumor phenotype may be the tumor microenvironment (TME), comprising dynamic and adaptative assortment of extracellular matrix components and non-neoplastic cells, which surround the tumor niche. Accumulating evidence shows that the TME can simultaneously support both tumor growth and metastasis and contribute to a certain state of resistance to treatment. In this review, we summarize the current knowledge of the TME of GEP-NETs and discuss the current therapeutic agents that target GEP-NETs and those that could be of interest in the (near) future.

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Anela Blažević, Johannes Hofland, Leo J Hofland, Richard A Feelders, and Wouter W de Herder

Small intestinal neuroendocrine tumours (SI-NETs) are neoplasms characterized by their ability to secrete biogenic amines and peptides. These cause distinct clinical pathology including carcinoid syndrome, marked by diarrhoea and flushing, as well as fibrosis, notably mesenteric fibrosis. Mesenteric fibrosis often results in significant morbidity by causing intestinal obstruction, oedema and ischaemia. Although advancements have been made to alleviate symptoms of carcinoid syndrome and prolong the survival of patients with SI-NETs, therapeutic options for patients with mesenteric fibrosis are still limited. As improved insight in the complex pathogenesis of mesenteric fibrosis is key to the development of new therapies, we evaluated the literature for known and putative mediators of fibrosis in SI-NETs. In this review, we discuss the tumour microenvironment, growth factors and signalling pathways involved in the complex process of fibrosis development and tumour progression in SI-NETs, in order to elucidate potential new avenues for scientific research and therapies to improve the management of patients suffering from the complications of mesenteric fibrosis.

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Anela Blažević, Wouter T Zandee, Gaston J H Franssen, Johannes Hofland, Marie-Louise F van Velthuysen, Leo J Hofland, Richard A Feelders, and Wouter W de Herder

Mesenteric fibrosis (MF) surrounding a mesenteric mass is a hallmark feature of small intestinal neuroendocrine tumours (SI-NETs). Since this can induce intestinal obstruction, oedema and ischaemia, prophylactic resection of the primary tumour and mesenteric mass is often recommended. This study assessed the predictors for mesenteric metastasis and fibrosis and the effect of MF and palliative surgery on survival. A retrospective analysis of 559 patients with pathologically proven SI-NET and available CT-imaging data was performed. Clinical characteristics, presence of mesenteric mass and fibrosis on CT imaging and the effect of palliative abdominal surgery on overall survival were assessed. We found that MF was present in 41.4%. Older age, 5-HIAA excretion ≥67 μmol/24 h, serum CgA ≥121.5 μg/L and a mesenteric mass ≥27.5 mm were independent predictors of MF. In patients ≤52 years, mesenteric mass was less often found in women than in men (39% vs 64%, P = 0.002). Corrected for age, tumour grade, CgA and liver metastasis, MF was not a prognostic factor for overall survival. In patients undergoing palliative surgery, metastasectomy of mesenteric mass or prophylactic surgery did not result in survival benefit. In conclusion, we confirmed known predictors of MF and mesenteric mass and suggest a role for sex hormones as women ≤52 years have less often a mesenteric mass. Furthermore, the presence of MF has no effect on survival in a multivariate analysis, and we found no benefit of metastasectomy of mesenteric mass or prophylactic surgery on overall survival.

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Julie Refardt, Wouter T Zandee, Tessa Brabander, Richard A Feelders, Gaston J.h Franssen, Leo J Hofland, Emanuel Christ, Wouter W de Herder, and Johannes Hofland

Sufficient expression of somatostatin receptor (SSTR) in well-differentiated neuroendocrine tumours (NETs) is crucial for treatment with somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) using radio-labelled SSAs. Impaired prognosis has been described for SSTR-negative NET patients, however studies comparing matched SSTR-positive and -negative subjects who have not received PRRT are missing. This retrospective analysis of two prospectively maintained NET databases aimed to compare matched metastatic grade 1 or 2 SSTR-positive and –negative NET patients. SSTR-negativity was defined as having insufficient tumour uptake on diagnostic SSTR imaging. Patients that underwent PRRT were excluded. Seventy-seven SSTR-negative and 248 SSTR-positive grade 1-2 NET patients were included. Median overall survival rates were significantly lower for SSTR-negative compared to SSTR-positive NET patients (53 months versus 131 months; p<0.001). To adjust for possible confounding by age, gender, grade and site of origin, 69 SSTR-negative NET patients were propensity score matched to 69 SSTR-positive NET patients. Group characteristics were similar, with the exception of SSTR-negative patients receiving more often chemotherapy and targeted treatment. The inferior survival outcome of SSTR-negative compared to SSTR-positive NET patients persisted with a median overall survival of 38 months versus 131 months (p=0.012). This relationship upheld when correcting for the main influencing factors of having a higher grade tumour or receiving surgery in a multivariate Cox regression analysis. In conclusion, we showed that propensity score-matched SSTR-negative NET patients continue to have a worse prognosis compared to SSTR-positive NET patients despite receiving more aggressive treatment. Differences in tumour biology likely underlie this survival deficit.

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Peter M van Koetsveld, Giovanni Vitale, Richard A Feelders, Marlijn Waaijers, Diana M Sprij-Mooij, Ronald R de Krijger, Ernst-Jan M Speel, Johannes Hofland, Steven W J Lamberts, Wouter W de Herder, and Leo J Hofland

Adrenocortical carcinoma (ACC) is an aggressive tumor with very poor prognosis. Novel medical treatment opportunities are required. We investigated the effects of interferon-β (IFN-β), alone or in combination with mitotane, on cell growth and cortisol secretion in primary cultures of 13 human ACCs, three adrenal hyperplasias, three adrenal adenomas, and in two ACC cell lines. Moreover, the interrelationship between the effects of IGF2 and IFN-β was evaluated. Mitotane inhibited cell total DNA content/well (representing cell number) in 7/11 (IC50: 38±9.2 μM) and cortisol secretion in 5/5 ACC cultures (IC50: 4.5±0.1 μM). IFN-β reduced cell number in 10/11 (IC50: 83±18 IU/ml) and cortisol secretion in 5/5 ACC cultures (IC50: 7.3±1.5 IU/ml). The effect of IFN-β on cell number included the induction of apoptosis. IFN-β strongly inhibited mRNA expression of STAR, CYP11A1, CYP17A1, and CYP11B1. Mitotane and IFN-β induced an additive inhibitory effect on cell number and cortisol secretion. IGF2 (10 nM) inhibited apoptosis and increased cell number and cortisol secretion. These effects were counteracted by IFN-β treatment. Finally, IFN-β inhibited IGF2 secretion and mRNA expression. In conclusion, IFN-β is a potent inhibitor of ACC cell growth in human primary ACC cultures, partially mediated by an inhibition of the effects of IGF2, as well as its production. The increased sensitivity of ACC cells to mitotane induced by treatment with IFN-β may open the opportunity for combined treatment regimens with lower mitotane doses. The inhibition of the expression of steroidogenic enzymes by IFN-β is a novel mechanism that may explain its inhibitory effect on cortisol production.

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Aura D Herrera-Martínez, Leo J Hofland, María A Gálvez Moreno, Justo P Castaño, Wouter W de Herder, and Richard A Feelders

Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.

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Maria Cristina De Martino, Peter M van Koetsveld, Richard A Feelders, Diana Sprij-Mooij, Marlijn Waaijers, Steven W J Lamberts, Wouter W de Herder, Annamaria Colao, Rosario Pivonello, and Leo J Hofland

Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone.

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Louis de Mestier, Anne Couvelard, Anela Blazevic, Olivia Hentic, Wouter W de Herder, Vinciane Rebours, Valérie Paradis, Philippe Ruszniewski, Leo J Hofland, and Jérôme Cros

The efficacy of alkylating agents (temozolomide, dacarbazine, streptozotocin) in patients with advanced neuroendocrine tumors (NETs) has been well documented, especially in pancreatic NETs. Alkylating agents transfer methyl adducts on DNA bases. Among them, O6-methylguanine accounts for many of their cytotoxic effects and can be repaired by the O6-methylguanine-methyltransferase (MGMT). However, whether the tumor MGMT status could be a reliable biomarker of efficacy of alkylating agents in NETs is still a matter of debate. Herein, we sought to provide a critical appraisal of the role of the MGMT status in NETs. After reviewing the molecular mechanisms of repair of DNA damage induced by alkylating agents, we aimed to comprehensively review the methods of determination of the MGMT status and its impact on prognosis, prediction of objective response and progression-free survival in patients with advanced digestive NETs treated by alkylating agents. About half of pancreatic NETs are MGMT-deficient, as determined by impaired tumor MGMT expression or by MGMT promoter methylation. Overall, while published studies are heterogeneous and mostly limited in size, they advocate that MGMT deficiency may be a relevant biomarker for increased objective response rate, prolonged progression-fee survival and overall survival in patients with advanced NETs treated by alkylating agents. While these data require confirmation in prospective controlled studies, future research should focus on the standardization of MGMT status assessment. Additional mechanisms of repair of DNA damages induced by alkylating agents should be explored in order to identify biomarkers complementary to MGMT and targets for potential antitumor synergy, such as PARP.

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Mieke E R Henfling, Aurel A Perren, Anja M Schmitt, Christiane M Saddig, Achim A Starke, Robert G Riedl, Yvonne M H Versleijen-Jonkers, Diana M Sprij-Mooij, Frans C S Ramaekers, Leo J Hofland, and Ernst-Jan M Speel

Clinical and molecular studies have implicated epidermal growth factor receptor (EGFR), insulin-like growth factor (IGF) and target of rapamycin (mTOR) signaling pathways in the regulation of pancreatic neuroendocrine tumor (PanNET) growth. Interpretation and comparison of these studies is complex due to clinical and molecular tumor heterogeneity. We therefore focused in this study on insulinomas, which we examined for mRNA and protein expression of EGFR, IGF and mTOR signaling pathway components by quantitative real-time PCR (n = 48) and immunohistochemistry (n = 86). Findings were compared with normal pancreatic islets and correlated with histopathological data and clinical outcome. Insulinomas showed low EGFR and high IGF2 expression. IGFBP2, IGFBP3 and IGFBP6 mRNA levels were 2- to 4-folds higher than those in islets. High protein expression of IGF2, IGF1R and INSR (in 51–92% of the tumors) and low-to-moderate expression of mTORC1 pathway proteins p-S6k and p-4EBP1 (7–28% of the tumors) were observed. Correlations were found between (1) ERK1 mRNA expression and that of numerous IGF pathway genes, (2) p-ERK and IGF1R protein expression and (3) decrease of IGF pathway components and both metastatic disease and shorter 10-year disease-free survival. In conclusion, our observations suggest that high expression of IGF signaling pathway components is a hallmark of insulinomas, but does not necessarily lead to increased mTOR signaling. Reduced expression of IGF pathway components may be an adverse prognostic factor in insulinomas.