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Open access

Susan Richter, Timothy J Garrett, Nicole Bechmann, Roderick J Clifton-Bligh, and Hans K Ghayee

Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.

Restricted access

Anela Blažević, Anand M Iyer, Marie-Louise F van Velthuysen, Johannes Hofland, Gaston J H Franssen, Richard A Feelders, Marina Zajec, Theo M Luider, Wouter W de Herder, and Leo J Hofland

Mesenteric metastases in small intestinal neuroendocrine tumors (SI-NETs) are associated with mesenteric fibrosis (MF) in a proportion of patients. MF can induce severe abdominal complications, and an effective preventive treatment is lacking. To elucidate possible novel therapeutic targets, we performed a proteomics-based analysis of MF. The tumor cell and stromal compartment of primary tumors and paired mesenteric metastases of SI-NET patients with MF (n = 6) and without MF (n = 6) was analyzed by liquid chromatography-mass spectrometry-based proteomics. Analysis of differential protein abundance was performed. Collagen alpha-1(XII) (COL12A1) and complement component C9 (C9) expression was evaluated by immunohistochemistry (IHC) in mesenteric metastases. A total of 2988 proteins were identified. Unsupervised hierarchical clustering showed close clustering of paired primary and mesenteric tumor cell samples. Comparing MF to non-MF samples, we detected differentially protein abundance solely in the mesenteric metastasis stroma group. There was no differential abundance of proteins in tumor cell samples or primary tumor stroma samples. Analysis of the differentially abundant proteins (n = 36) revealed higher abundance in MF samples of C9, various collagens and proteoglycans associated with profibrotic extracellular matrix dysregulation and signaling pathways. Proteins involved in fatty acid oxidation showed a lower abundance. COL12A1 and C9 were confirmed by IHC to have significantly higher expression in MF mesenteric metastases compared to non-MF. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development. In conclusion, proteome profiles of SI-NETs with and without MF differ primarily in the stromal compartment of mesenteric metastases. Analysis of differentially abundant proteins revealed possible new signaling pathways involved in MF development.

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Xuguang Zhu, Li Zhao, Woo Kyung Lee Doolittle, and Sheue-yann Cheng

Anaplastic thyroid cancer (ATC) is one of the most aggressive solid cancers in humans, with limited treatment options. Recent studies suggest that cancer stem cell (CSC) activity contributes to therapeutic resistance and recurrence of ATC. We show that the expression of the endogenous thyroid hormone receptor β gene (THRB) is silenced in ATC and demonstrate that the exogenously expressed TRβ suppresses CSC activity. Decitabine is one of the demethylation agents to treat myelodysplastic syndrome and acute myeloid leukemia patients and is currently in clinical trials for hematopoietic malignancies and solid tumors. We aim to show that the re-expression of the endogenous THRB gene by decitabine can attenuate CSC activity to block ATC tumor growth. We treated ATC cell lines derived from human ATC tumors (11T and 16T cells) with decitabine and evaluated the effects of the reactivated endogenous TRβ on CSC activity in vitro and in vivo xenograft models. We found that treatment of 11T and 16T cells with decitabine reactivated the expression of endogenous TRβ, as evidenced by western blot and immunohistochemical analyses. The expressed TRβ inhibited cell proliferation by arresting cells at the S phase, increased apoptotic cell death by upregulation of cleaved caspase-3, and markedly suppressed the expression of CSC regulators, including cMYC, ALDH, SOX2, CD44, and β-catenin. Decitabine also inhibited xenograft tumor growth by suppressing CSC activity, inhibiting cancer cell proliferation, and increasing apoptosis. Our findings suggest that re-expression of the endogenous TRβ is a novel therapeutic approach for ATC via suppression of CSC activity.

Free access

Marilina Romeo, Giorgia Spaggiari, Chiara Furini, Antonio R M Granata, Angela Toss, Manuela Simoni, and Daniele Santi

Cancer-related diagnosis and treatments can profoundly affect every aspect of an individual’s life. The negative impact on the sexual sphere can manifest with onset or worsening of the most frequent male form of sexual dysfunction, that is the erectile dysfunction (ED), with an estimated incidence ranging from 40 to 100% in patients living with cancer. Cancer and ED are strictly related for many reasons. First, the psychological distress, the so-called 'Damocles syndrome', afflicting cancer patients contributes to ED onset. Second, all cancer therapies can variably lead to sexual dysfunction, even more than the disease itself, having both direct or indirect effects on sexual life. Indeed, alongside pelvic surgery and treatments directly impairing the hypothalamus–pituitary–gonadal axis, the altered personal-body-image frequently experienced by people living with cancer may represent a source of distress contributing to sexual dysfunction. It is undeniable that sexual issues are currently neglected or at least under-considered in the oncological setting, mainly due to the subjective lack of preparation experienced by healthcare professionals and to scant information provided to oncological patients on this topic. To overcome these management problems, a new multidisciplinary medical branch called ‘oncosexology’ was set up. The aim of this review is to comprehensively evaluate ED as an oncology-related morbidity, giving new light to sexual dysfunction management in the oncological setting.

Free access

Wenzel M Hackeng, Lodewijk A A Brosens, and Koen M A Dreijerink

Insulinomas are rare functional pancreatic neuroendocrine tumors. While most insulinomas are indolent and cured after surgery, 10–15% of cases show aggressive or malignant tumor behavior and metastasize locally or to distant organs. Patients with metastatic insulinoma survive significantly shorter. Recognizing aggressive insulinomas can help to predict prognosis, guide therapy and determine follow-up intensity after surgery. This review offers a summary of the literature on the significant clinical, pathological, genetic and epigenetic differences between indolent and aggressive insulinomas. Aggressive insulinomas are characterized by rapid onset of symptoms, larger size, expression of ARX and alpha-1-antitrypsin and decreased or absent immunohistochemical expression of insulin, PDX1 and GLP-1R. Moreover, aggressive insulinomas often harbor ATRX or DAXX mutations, the alternative lengthening of telomeres phenotype and chromosomal instability. Tumor grade and MEN1 and YY1 mutations are less useful for predicting behavior. Aggressive insulinomas have similarities to normal alpha-cells and non-functional pancreatic neuroendocrine tumors, while indolent insulinomas remain closely related to normal beta-cells. In conclusion, indolent and aggressive insulinoma are different entities, and distinguishing these will have future clinical value in determining prognosis and treatment.

Restricted access

Xumeng Wang, Tianxing Ying, Jimeng Yuan, Yue Wang, Xingyun Su, Shitu Chen, Yurong Zhao, Yuanyuan Zhao, Jinghao Sheng, Lisong Teng, Chi Luo, and Weibin Wang

Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30%-50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-QPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.

Open access

Yuanliang Yan, Qiuju Liang, Yuanhong Liu, Shangjun Zhou, and Zhijie Xu

Immunotherapy has shown promising efficacy for breast cancer (BC) patients. Yet the predictive biomarkers for immunotherapy response remain lacking. Based on two GEO datasets, 53 differentially expressed genes associated with durvalumab treatment response were identified. Using least absolute shrinkage and selection operator (LASSO) and univariate Cox regression, four genes (COL12A1, TNN, SCUBE2, and FDCSP) revealed prognostic value in the TCGA BC cohort. COL12A1 outperformed the others, without overlap in its survival curve. Survival analysis by Kaplan–Meier plotter demonstrated that COL12A1 was negatively associated with BC patients’ prognosis. A COL12A1-based nomogram was further developed to predict the overall survival in BC patients. The calibration plot revealed an optimal agreement between nomogram prediction and actual observation. Moreover, COL12A1 expression was significantly up-regulated in BC tissues and COL12A1 knockdown impaired the proliferation of MDA-MB-231 and BT549 cells. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment analysis pathway indicated that the function of COL12A1 was related to immunity-related pathways. Immunological analyses illustrated that COL12A1 was correlated with M2 macrophage infiltration and M2 macrophage markers (transforming growth factor beta 1 (TGFB1), interleukin-10, colony stimulating factor 1 receptor (CSF1R) and CD163) in BC. Immunohistochemistry staining further revealed a highly positive relationship of COL12A1 with TGF-β1. The co-incubated models of BC cells and M2 macrophges showed COL12A1 knockdown suppressed M2 macrophage infiltration. Additionally, silencing COL12A1 suppressed TGF-B1 protein expression, and treating with TGFB1 could reverse the inhibitory effects on M2 macrophage infiltration by COL12A1 knockdown. Using immunotherapy datasets, we also found elevated expression of COL12A1 predicted poor response to anti-PD-1/PD-L1 therapy. These results reinforce the current understanding of COL12A1’s roles in tumorigenesis and immunotherapy response in BC.

Open access

Jennifer R Eads, Thorvardur R Halfdanarson, Tim Asmis, Andrew M. Bellizzi, Emily K Bergsland, Arvind Dasari, Ghassan El-Haddad, Michael Frumovittz, Joshua Meyer, Erik Mittra, Sten Myrehaug, Eric Nakakura, Nitya Raj, Heloisa P Soares, Brian Untch, Namrata Vijayvergia, and Jennifer A Chan

High grade neuroendocrine tumors (G3 NET) and neuroendocrine carcinomas (NEC) are a rare disease entity for which there is a limited amount of prospective data available. It has also been relatively recent that a distinction has been made between G3 NET and NEC, further complicating the approach for management. Due to the overall lack of data in this space, much of the practice for treatment of these tumors is based on expect opinion. The North American Neuroendocrine Tumor Society (NANETS) is an organization composed of experts who specialize in the management of these tumors. In an effort to provide further guidance to the oncology community in regard to the management of these rare tumors, NANETS convened a panel of experts from medical oncology, surgery, interventional radiology, nuclear medicine, radiology, pathology and radiation oncology to address critical issues surrounding the management of G3 NET and NEC that would benefit from expert consensus opinion. Here we present the recommendations from this panel of neuroendocrine experts in regard to the management of high grade, extra-pulmonary neuroendocrine tumors (G3 NET) and neuroendocrine carcinomas (NEC).

Open access

Maria Angela De Stefano, Tommaso Porcelli, Martin Schlumberger, and Domenico Salvatore

The three deiodinase selenoenzymes are key regulators of intracellular thyroid hormone (TH) levels. The two TH-activating deiodinases (type 1 deiodinase and type 2 deiodinase (D2)) are normally expressed in follicular thyroid cells and contribute to overall TH production. During thyroid tumorigenesis, the deiodinase expression profile changes to customize intracellular TH levels to different requirements of cancer cells. Differentiated thyroid cancers overexpress the TH-inactivating type 3 deiodinase (D3), likely to reduce the TH signaling within the tumor. Strikingly, recent evidence suggests that during the late stage of thyroid tumorigenesis, D2 expression raises and this, together with a reduction in D3 expression levels, increases TH intracellular signaling in dedifferentiated thyroid cancers. These findings call into question the different functions of TH in the various stages of thyroid cancers.

Open access

Dahlia F Davidoff, Eugénie S Lim, Diana E Benn, Yuvanaa Subramaniam, Eleanor Dorman, John R Burgess, Scott A Akker, and Roderick J Clifton-Bligh

Phaeochromocytoma and paraganglioma are highly heritable tumours; half of those associated with a germline mutation are caused by mutations in genes for Krebs’s cycle enzymes, including succinate dehydrogenase (SDH). Inheritance of SDH alleles is assumed to be Mendelian (probability of 50% from each parent). The departure from transmission of parental alleles in a ratio of 1:1 is termed transmission ratio distortion (TRD). We sought to assess whether TRD occurs in the transmission of SDHB pathogenic variants (PVs). This study was conducted with 41 families of a discovery cohort from Royal North Shore Hospital, Australia, and 41 families from a validation cohort from St. Bartholomew’s Hospital, United Kingdom (UK). Inclusion criteria were a clinically diagnosed SDHB PV and a pedigree available for at least two generations. TRD was assessed in 575 participants with the exact binomial test. The transmission ratio for SDHB PV was 0.59 (P = 0.005) in the discovery cohort, 0.67 (P < 0.001) in the validation cohort, and 0.63 (P < 0.001) in the combined cohort. No parent-of-origin effect was observed. TRD remained significant after adjusting for potential confounders: 0.67 (P < 0.001) excluding families with incomplete family size data; 0.58 (P < 0.001) when probands were excluded. TRD was also evident for SDHD PVs in a cohort of 81 patients from 13 families from the UK. The reason for TRD of SDHB and SDHD PVs is unknown, but we hypothesize a survival advantage selected during early embryogenesis. The existence of TRD for SDHB and SDHD has implications for reproductive counselling, and further research into the heterozygote state.