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Florian Bösch, Katharina Brüwer, Annelore Altendorf-Hofmann, Christoph J Auernhammer, Christine Spitzweg, C Benedikt Westphalen, Stefan Boeck, Gabriele Schubert-Fritschle, Jens Werner, Volker Heinemann, Thomas Kirchner, Martin Angele and Thomas Knösel

Cancer immunotherapy has evolved major breakthroughs in the last years. The cell-surface receptor programmed death-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1), have been detected in various cancer types. However, the analysis on gastroenteropancreatic neoplasia (GEP-NENs) is limited. Therefore, the aim of this study was to characterize GEP-NENs with regard to PD-1/PD-L1 pathway and tumor-infiltrating lymphocytes (TILs). On protein level, we examined TILs, PD-1 and PD-L1 expression in tumor tissue of 244 GEP-NENs using immunohistochemistry. Expression levels were correlated with clinicopathological parameters including long-term survival in an observational study. In total, 244 patients could be included. Most of the patients had a NEN of the small intestine (52.5%) or the pancreas (29.5%). All tumors could be graded by their morphology and Ki67 index, with 57.8% G1, 34% G2 and 8.2% G3 tumors. High TILs (19.6%) and high PD-1 (16.1%) expression showed a significant correlation with shorter patient survival (P < 0.05) and with a higher grading. Furthermore, expression of PD-L1 (8.7%) showed a trend to shorter patient survival. High TILs and PD-1 expression are significantly associated with shorter patient survival and higher grading in GEP-NENs. PD-L1 expression showed a trend to shorter patient survival. Immunotherapy might be a promising therapeutic approach in GEP-NENs especially in tumors with high TILs.

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Zhe Wang, Ke Ma, Steffie Pitts, Yulan Cheng, Xi Liu, Xiquan Ke, Samuel Kovaka, Hassan Ashktorab, Duane T Smoot, Michael Schatz, Zhirong Wang and Stephen J Meltzer

Circular RNAs (circRNAs) are a new class of RNA involved in multiple human malignancies. However, limited information exists regarding the involvement of circRNAs in gastric carcinoma (GC). Therefore, we sought to identify novel circRNAs, their functions and mechanisms in gastric carcinogenesis. We analyzed next-generation RNA sequencing data from GC tissues and cell lines, identifying 75,201 candidate circRNAs. Among these, we focused on one novel circRNA, circNF1, which was upregulated in GC tissues and cell lines. Loss- and gain-of-function studies demonstrated that circNF1 significantly promotes cell proliferation. Furthermore, luciferase reporter assays showed that circNF1 binds to miR-16, thereby derepressing its downstream target mRNAs, MAP7 and AKT3. Targeted silencing or overexpression of circNF1 had no effect on levels of its linear RNA counterpart, NF1. Taken together, these results suggest that circNF1 acts as a novel oncogenic circRNA in GC by functioning as a miR-16 sponge.

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Rabii Ameziane El Hassani, Camille Buffet, Sophie Leboulleux and Corinne Dupuy

At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct ‘professional’ ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.

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Matthias Beyens, Timon Vandamme, Marc Peeters, Guy Van Camp and Ken Op de Beeck

The mammalian target of rapamycin (mTOR) is part of the phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt)/mTOR signaling. The PI3K/Akt/mTOR pathway has a pivotal role in the oncogenesis of neuroendocrine tumors (NETs). In addition, vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) drive angiogenesis in NETs and therefore contributes to neuroendocrine tumor development. Hence, mTOR and angiogenesis inhibitors have been developed. Everolimus, a first-generation mTOR inhibitor, has shown significant survival benefit in advanced gastroenteropancreatic NETs. Sunitinib, a pan-tyrosine kinase inhibitor that targets the VEGF receptor, has proven to increase progression-free survival in advanced pancreatic NETs. Nevertheless, primary and acquired resistance to rapalogs and sunitinib has limited the clinical benefit for NET patients. Despite the identification of multiple molecular mechanisms of resistance, no predictive biomarker has made it to the clinic. This review is focused on the mTOR signaling and angiogenesis in NET, the molecular mechanisms of primary and acquired resistance to everolimus and sunitinib and how to overcome this resistance by alternative drug compounds.

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Zhi Long, Yinan Li, Yu Gan, Dongyu Zhao, Guangyu Wang, Ning Xie, Jessica M Lovnicki, Ladan Fazli, Qi Cao, Kaifu Chen and Xuesen Dong

Homeobox A10 (HOXA10) is an important transcription factor that regulates the development of the prostate gland. However, it remains unknown whether it modulates prostate cancer (PCa) progression into castrate-resistant stages. In this study, we have applied RNA in situ hybridization assays to demonstrate that downregulation of HOXA10 expression is associated with castrate-resistant PCa. These findings are supported by public RNA-seq data showing that reduced HOXA10 expression is correlated with poor patient survival. We show that HOXA10 suppresses PCa cell proliferation, anchorage colony formation and xenograft growth independent to androgens. Using AmpliSeq transcriptome sequencing, we have found that gene groups associated with lipid metabolism and androgen receptor (AR) signaling are enriched in the HOXA10 transcriptome. Furthermore, we demonstrate that HOXA10 suppresses the transcription of the fatty acid synthase (FASN) gene by forming a protein complex with AR and prevents AR recruitment to the FASN gene promoter. These results lead us to conclude that downregulation of HOXA10 gene expression may enhance lipogenesis to promote PCa cell growth and tumor progression to castrate-resistant stage.

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Willem E Corver and Hans Morreau

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Giorgio Secreto, Alessandro Girombelli and Vittorio Krogh

The aim of this review is to highlight the pivotal role of androgen excess in the development of breast cancer. Available evidence suggests that testosterone controls breast epithelial growth through a balanced interaction between its two active metabolites: cell proliferation is promoted by estradiol while it is inhibited by dihydrotestosterone. A chronic overproduction of testosterone (e.g. ovarian stromal hyperplasia) results in an increased estrogen production and cell proliferation that are no longer counterbalanced by dihydrotestosterone. This shift in the androgen/estrogen balance partakes in the genesis of ER-positive tumors. The mammary gland is a modified apocrine gland, a fact rarely considered in breast carcinogenesis. When stimulated by androgens, apocrine cells synthesize epidermal growth factor (EGF) that triggers the ErbB family receptors. These include the EGF receptor and the human epithelial growth factor 2, both well known for stimulating cellular proliferation. As a result, an excessive production of androgens is capable of directly stimulating growth in apocrine and apocrine-like tumors, a subset of ER-negative/AR-positive tumors. The key role of androgen excess in the genesis of different subtypes of breast cancer has significant clinical implications for both treatment and prevention. Our belief stems from a thorough analysis of the literature, where an abundance of evidence is present to justify a clinical trial that would investigate the effectiveness of treating the underlying excessive androgen production.

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Ji Won Kim, Dharmendra K Yadav, Soo Jin Kim, Moo-Yeol Lee, Jung-Min Park, Bum Seok Kim, Mi-hyun Kim, Hyeung-geun Park and Keon Wook Kang

GV1001, a 16-amino acid fragment of the human telomerase reverse transcriptase catalytic subunit (hTERT), has been developed as an injectable formulation of cancer vaccine. Here, we revealed for the first time that GV1001 is a novel ligand for gonadotropin-releasing hormone receptor (GnRHR). The docking prediction for GV1001 against GnRHR showed high binding affinity. Binding of GV1001 to GnRHR stimulated the Gαs-coupled cAMP signaling pathway and antagonized Gαq-coupled Ca2+ release by leuprolide acetate (LA), a GnRHR agonist. Repeated injection of GV1001 attenuated both serum testosterone level and seminal vesicle weight via desensitization of hypothalamic–pituitary–gonadal (HPG) axis. We then tested whether GV1001 has an inhibitory effect on tumor growth of LNCaP cells, androgen receptor–positive human prostate cancer (PCa) cells. GV1001 significantly inhibited tumor growth and induced apoptosis in LNCaP-implanted xenografts. Interestingly, mRNA expressions of matrix metalloproteinase 2 and matrix metalloproteinase 9 were suppressed by GV1001, but not by LA. Moreover, GV1001 significantly inhibited the proliferation and migration of PCa cells and induced apoptosis in a concentration-dependent manner. Our findings suggest that GV1001 functions as a biased GnRHR ligand to selectively stimulate the Gαs/cAMP pathway, with anti-proliferative and anti-migratory effects on human PCa.

Open access

Dawei Wu, Dongwei Lv, Ting Zhang, Lianying Guo, Fangli Ma, Caihua Zhang, Guofeng Lv and Lin Huang

Ewing sarcoma family tumors (ESFTs) are a group of aggressive and highly metastatic tumors lacking efficient therapies. Insulin-like growth factor 1 receptor (IGF1R) blockade is one of the most efficient targeting therapy for ESFTs. However, the appliance is obstructed by drug resistance and disease recurrence due to the activation of insulin receptor (IR) signaling induced by IGF1R blockade. Herein β-elemene, a compound derived from natural plants, exhibited a remarkable proliferation repression on ESFT cells, which was weakened by a caspase inhibitor Z-VAD. β-elemene in combination with IGF1R inhibitors enhanced markedly the repression on cellular proliferation and mTOR activation by IGF1R inhibitors and suppressed the PI3K phosphorylation induced by IGF1R inhibitors. To investigate the mechanisms, we focused on the effects of β-elemene on IR signaling pathway. β-elemene significantly suppressed the insulin-driven cell growth and the activation of mTOR and PI3K in tumor cells, while the toxicity to normal hepatocytes was much lower. Further, the phosphorylation of IR was found to be suppressed notably by β-elemene specifically in tumor cells other than normal hepatocytes. In addition, β-elemene inhibited the growth of ESFT xenografts in vivo, and the phosphorylation of IR and S6 ribosomal protein was significantly repressed in the β-elemene-treated xenografts. These data suggest that β-elemene targets IR phosphorylation to inhibit the proliferation of tumor cells specifically and enhance the effects of IGF1R inhibitors. Thus, this study provides evidence for novel approaches by β-elemene alone or in combination with IGF1R blockades in ESFTs and IR signaling hyperactivated tumors.

Free access

G Mantovani, D Treppiedi, E Giardino, R Catalano, F Mangili, P Vercesi, M Arosio, A Spada and E Peverelli

Although generally benign, pituitary tumors are frequently locally invasive, with reduced success of neurosurgery and unresponsive to pharmacological treatment with somatostatin or dopamine analogues. The molecular basis of the different biological behavior of pituitary tumors are still poorly identified, but a body of work now suggests that the activity of specific cytoskeleton proteins is a key factor regulating both the invasiveness and drug resistance of these tumors. This review recapitulates the experimental evidence supporting a role for the actin-binding protein filamin A (FLNA) in the regulation of somatostatin and dopamine receptors expression and signaling in pituitary tumors, thus in determining the responsiveness to currently used drugs, somatostatin analogues and dopamine receptor type 2 agonists. Regarding the regulation of invasive behavior of pituitary tumoral cells, we bring evidence to the role of the actin-severing protein cofilin, whose activation status may be modulated by dopaminergic and somatostatinergic drugs, through FLNA involvement. Molecular mechanisms involved in the regulation of FLNA expression and function in pituitary tumors will also be discussed.