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Giovanni Vitale, Alessandra Dicitore, Concetta Sciammarella, Sergio Di Molfetta, Manila Rubino, Antongiulio Faggiano and Annamaria Colao

Somatostatin analogs have an important role in the medical therapy of neuroendocrine tumors (NETs). Octreotide and lanreotide, both somatostatin analogs binding with high affinity for the somatostatin receptor (SSTR)2, can control symptoms in functional NETs. In addition, these compounds, because of their antiproliferative effects, can stabilize growth of well-differentiated NETs. Pasireotide is a novel multireceptor-targeted somatostatin analog with high affinity for SSTR1, 2, 3, and 5. This review provides an overview of the state of the art of pasireotide in the treatment of NETs, with the aim of addressing clinical relevance and future perspectives for this molecule in the management of NETs.

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Giovanni Vitale, Germano Gaudenzi, Alessandra Dicitore, Franco Cotelli, Diego Ferone and Luca Persani

Tumor models have a relevant role in furthering our understanding of the biology of malignant disease and in preclinical cancer research. Only few models are available for neuroendocrine tumors (NETs), probably due to the rarity and heterogeneity of this group of neoplasms. This review provides insights into the current state-of-the-art of zebrafish as a model in cancer research, focusing on potential applications in NETs. Zebrafish has a complex circulatory system similar to that of mammals. A novel angiogenesis assay based on the injection of human NET cell lines (TT and DMS79 cells) into the subperidermal space of the zebrafish embryos has been developed. Proangiogenic factors locally released by the tumor graft affect the normal developmental pattern of the subintestinal vessels by stimulating the migration and growth of sprouting vessels toward the implant. In addition, a description of the striking homology between zebrafish and humans of molecular targets involved in tumor angiogenesis (somatostatin receptors, dopamine receptors, mammalian target of rapamycin), and currently used as targeted therapy of NETs, is reported.

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Annemiek Walenkamp, Guillermo Crespo, Felipe Fierro Maya, Reidar Fossmark, Peter Igaz, Anja Rinke, Gianluca Tamagno, Giovanni Vitale, Kjell Öberg and Tim Meyer

In the past few years, there have been advances in the treatment of neuroendocrine tumours (NETs) and improvements in our understanding of NET biology. However, the benefits to patients have been relatively modest and much remains yet to be done. The ‘Hallmarks of Cancer’, as defined by Hanahan and Weinberg, provide a conceptual framework for understanding the aberrations that underlie tumourigenesis and to help identify potential targets for therapy. In this study, our objective is to review the major molecular characteristics of NETs, based on the recently modified ‘Hallmarks of Cancer’, and highlight areas that require further research.

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Giovanni Vitale, Germano Gaudenzi, Luisa Circelli, Marco F Manzoni, Andrea Bassi, Niccolò Fioritti, Antongiulio Faggiano, Annamaria Colao and on behalf of NIKE Group

Medullary thyroid carcinoma is a neuroendocrine tumour originating from parafollicular C cells accounting for 5–10% of thyroid cancers. Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid carcinoma. These drugs increase progression-free survival; however, they are often poorly tolerated and most treatment responses are transient. Animal models are indispensable tools for investigating the pathogenesis, mechanisms for tumour invasion and metastasis and new therapeutic approaches for cancer. Unfortunately, only few models are available for medullary thyroid carcinoma. This review provides an overview of the state of the art of animal models in medullary thyroid carcinoma and highlights future developments in this field, with the aim of addressing salient features and clinical relevance.

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Germano Gaudenzi, Silvia Carra, Alessandra Dicitore, Maria Celeste Cantone, Luca Persani and Giovanni Vitale

Neuroendocrine tumors (NETs) are a class of rare and heterogeneous neoplasms that originate from the neuroendocrine system. In several cases, these neoplasms can release bioactive hormones leading to characteristic clinical syndromes and hormonal dysregulations with detrimental impact on the quality of life and survival of these patients. Only few animal models are currently available to investigate pathogenesis, progression and functional syndromes in NETs and to identify new therapeutic strategies. The tropical teleost zebrafish (Danio rerio) is a popular vertebrate model system that offers unique advantages for the study of several biological processes, ranging from embryonic development to human diseases such as cancer. In this review, we summarize recent advances on zebrafish models for NET preclinical research that take advantage of modern genetic and transplantable technologies. In the future, these tools may have a role in the treatment decision-making and tertiary prevention of NETs.

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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.