Endocrine-related cancer最新文献

Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with poor survival rates and few treatment options. Preclinical models are indispensable to further strengthen our understanding of disease progression and development of novel therapeutic treatments. Here, we report the establishment of a new cell line named ZUC-1 originating from the resection of an advanced primary ACC and its characterization at the genomic, cellular and molecular level. ZUC-1 cells were successfully propagated as monolayer cultures and three-dimensional spheroids. LC-MS/MS analysis revealed for ZUC-1 cells co-secretion of cortisol, aldosterone and testosterone and the model represented in direct comparison with other current ACC pre-clinical models furthermore significantly elevated expression of SF-1, CYP11B1 and CYP11B2 genes. Whole genome sequencing identified various mutations in genes linked to DNA repair/stress response, stemness, but also steroidogenesis. Interestingly, ZUC-1 represents genotypic and phenotypic variations which might be of interest beyond ACC including congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS). Moreover, 18OH and 18-oxo-cortisol release was detected in ZUC-1, conditions which are often linked to hyperaldosteronism, but forskolin, potassium and at higher concentration angiotensin II modulability of CYP11B2 for this model is retained. ZUC-1 spheroids exhibited furthermore an intra-spheroidal heterogenous mix of canonical and non-canonical Wnt pathway activation. We conclude that due to its origin and unique geno- and phenotypes, ZUC-1 represents an intriguing model to further gain basic understanding of adrenal function,the pathogenesis of ACC, but it might be also of interest in context of CAH and PCOS.

Loss-of-function (LOF) germline AIP variants are the main genetic cause of familial isolated pituitary adenoma and gigantism. A role for this defect in other neoplasms has been suggested, but remains unclear. We investigated the frequency, associated phenotypes, and in vitro functional effects of germline AIP variants in a cohort of Mexican patients with neuroendocrine neoplasms (NENs). Blood DNA samples from 101 adults (70.3% females) with isolated or syndromic NENs (50 with pituitary neuroendocrine tumors, PitNETs) were analyzed using a next generation sequencing panel. Targeted Sanger screening was carried out in additional family members and tumor samples. Missense and intronic variants were functionally assessed via cycloheximide chase assays or quantitative polymerase chain reaction plus sequence analysis of blood cDNA, as appropriate. Two rare likely benign defects (c.787 + 9C>T and p.T231M), two variants of uncertain significance (p.R106C and p.V291_L292del), one likely pathogenic (LP, p.C238Y), and one pathogenic (p.R304*) variant were found in six cases (5.9%). One individual was diagnosed with multiple gastric NENs and five carried PitNETs. Variant p.V291_L292del produced an unstable protein (P < 0.0001 for half-life curve, compared with wild type) and was reclassified to LP. Loss of heterozygosity in a gastric neuroendocrine tumor and nonsignificantly increased protein stability were observed for p.R106C. No deleterious effects were documented for c.787 + 9C>T. In conclusion, we determined the prevalence of AIP variants in a cohort of NENs and reclassified one VUS to LP. Our findings support the causal association of AIP LOF with PitNETs, but cannot rule out a role for AIP in other NENs.

There are currently few treatment options available for advanced neuroendocrine neoplasms (NENs). When treating metastatic renal cancer, the combination of lenvatinib with everolimus has shown noticeably greater success than monotherapy. Clarifying the synergistic effects of lenvatinib and everolimus on NENs and investigating the underlying processes were the goals of this study. Lenvatinib and everolimus were tested for their synergistic inhibitory effects on NEN cells in vitro using CCK-8, colony formation, wound healing, flow cytometry, and tube formation. In vivo evaluation of the combined inhibitory effects was conducted using a xenograft mouse model. Western blot analysis was used to look into the main regulatory molecules implicated in this synergy, and clinical case studies were used to quantify the clinical benefits. The combination of lenvatinib and everolimus showed a synergistic anti-tumor impact in vivo and suppressed cell proliferation, colony formation, cell migration, angiogenesis, and promoted apoptosis in vitro. Notably, in patients with advanced NENs who developed resistance after many lines of therapy (>2nd line), this combination successfully postponed the advancement of their disease. Mechanistically, both medications increased the expression of ITGB4 and inhibited 4EBP1 phosphorylation; their combined inhibitory effects on NENs were lessened when ITGB4 was knocked down. These findings indicate that lenvatinib and everolimus act synergistically to inhibit NEN proliferation and migration and to induce apoptosis in vitro, with robust synergistic activity also evident in vivo. This synergy appears to be mediated, at least in part, through the upregulation of ITGB4.

Multiple endocrine neoplasia type 2 (MEN2) is caused by germline RET mutations and is characterized by the presence of medullary thyroid cancer (MTC) associated or not with other endocrine neoplasias. MEN2 is classified as MEN2A, including different variants, and MEN2B. The aim of the present study was to evaluate the impact of the RET genetic screening in redefining the prevalence of the different MEN2 variants inside the MEN2A group. This study included 223 MEN2 families: 202 MEN2A (55 MEN2A classical, 3 MEN2A + lichen cutaneous amyloidosis (CLA), 5 MEN2A + Hirschsprung disease (HD) and 139 FMTC variants) and 21 MEN2B. RET germline mutations found in MEN2A classical variant, as well as in MEN2A + CLA and MEN2A + HD, were the 'high-risk' category in most cases, while only 5/139 RET-mutated FMTC families showed a 'high-risk' category mutation. The most frequent mutation in the FMTC variant was the p.Val804Met (62/139). Among all, 116 families had a known history of hereditary disease (group A) at diagnosis and 107 had an apparently sporadic form of MTC (group B). Different MEN2A variants and RET ATA risk level category mutations were observed in the two groups. In conclusion, we demonstrated that the FMTC is the most prevalent MEN2A variant; 'moderate-risk' RET mutations, particularly non-cysteine mutations, are almost exclusively present in the FMTC variant; about 50% of hereditary MTC kindreds are primarily discovered by the RET genetic screening, confirming the clinical utility of performing this analysis in all cases of MTC.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, chromaffin cell-derived tumours of the adrenal medulla or paraganglia. Germline pathogenic variants in succinate dehydrogenase subunit B (SDHB) are most prevalent and associated with malignancy and poor prognosis. Treatment options are limited, and therapy development is hindered by knowledge gaps concerning the pathomechanism and lack of suitable models. Previously, homozygous sdhb mutant zebrafish larvae showed disease characteristics, and adult heterozygous mutants represented human heterozygous SDHB carriers, portraying low-grade systemic succinate accumulation. Since spontaneous PPGL formation remains absent, we applied vitamin C supplementation as potential trigger to induce tumourigenesis in adult heterozygous sdhb mutant zebrafish. In addition, sdhb mutant larvae were exposed to vitamin C to investigate dose-dependent effects in an sdhb-deficient context. Twelve percent of vitamin C-supplemented adult sdhb mutants showed local proliferation of chromaffin cells with tissue-specific sdhb deficiency. Furthermore, metabolite profiling showed an increase in succinate/fumarate ratios upon vitamin C in heterozygous sdhb mutants. Gene expression analysis showed activation of the hypoxia-inducible factor pathway in larval and adult zebrafish. In addition, high dose vitamin C increased nrf2a expression, representing oxidative stress, in homozygous and heterozygous sdhb mutants. Ultimately, we have successfully employed vitamin C supplementation to initiate chromaffin cell proliferation in adult heterozygous sdhb mutant zebrafish, resembling early-stage PPGL tumourigenesis. Furthermore, we gained insights into underlying mechanisms, including HIF stabilisation, demethylation, oxidative stress, iron metabolism and glucose transport. Our model provides a unique platform to investigate possible triggers for PPGL development in the human mutation carrier state and investigate early stages of tumourigenesis.

The intracellular molecular networks are highly complex and plastic. Yet, they obey the network principles discovered by systems biology. Precise mathematical models of some networks enable one to predict how molecular properties determine the function and malfunction of the network. However, the complexity is even greater than this: due to selection in evolutionary biology, the molecular networks are not only causal to cell function, but also caused by the requirement that the cell's functions be optimal. We discuss how the combination of complexity, plasticity, and this circular causality makes the networks similar to trained artificial neural networks. Causation by purpose might thereby dominate over causation by mechanism. Comparison of challenges that may cause or cure disease with actual challenges in evolutionary, developmental, or cell biology, and assessment of the learned responses thereto, might add another interesting layer of systems biology.

With increased use of somatostatin analogue (SSA) PET/CT, the prevalence of incidentaloma - at present approximately 4.5% - is anticipated to rise. As malignancy has been reported in 13% of all cases, these incidentaloma are clinically relevant. However, because of publication bias, prevalence is probably underestimated and the malignancy rate overestimated. Therefore, we assessed the prevalence, cause, malignancy rate, and tracer uptake intensity on 68Ga-DOTANOC PET. All 68Ga-DOTANOC PET/CT protocols in adults, performed between 2017 and 2024 at Antwerp University Hospital, were retrospectively screened for incidentaloma. Patient records were examined to determine the cause of non-physiological increased tracer uptake. A total of 1,951 68Ga-DOTANOC PET/CTs were performed in 1,102 subjects. A total of 145 incidentaloma (13.2%) were described in 136 subjects (mean age 64 ± 13 years; F/M 82/54), most commonly in the thyroid (n = 43), brain (n = 31), prostate (n = 23), and breast (n = 11). The cause of pathological tracer uptake was evaluated by additional imaging in 55% of incidentaloma, whereby benign thyroid nodules, meningioma, benign prostatic hyperplasia, and breast fibroma and carcinoma were the most common findings, respectively. The malignancy rate was low (6%), comprising two breast cancers, one prostate cancer, one renal cell carcinoma, and one lung cancer. This is the largest single-centre study describing the prevalence and cause of 68Ga-DOTANOC incidentaloma to date. While the prevalence is significantly higher (13.2%) than described in previous studies (4.5%), the malignancy rate was significantly lower (6 versus 13%), as was expected due to publication bias, and no thyroid cancer was diagnosed.

Locoregional therapies are a standard treatment for neuroendocrine tumors (NET) with predominant liver metastases. The efficacy of transarterial chemoembolization (TACE) using streptozotocin (STZ) has been poorly compared to transarterial embolization (TAE). Predictive biomarkers of TACE efficacy have never been explored. We studied all patients with pancreatic (panNET) or small intestine (siNET) NET and liver metastases treated between 2006 and 2022 using a standardized protocol of TACE-STZ (1,500 mg/m2) or TAE. The primary endpoint was the RECIST 1.1-defined objective response rate (ORR). The variables associated with ORR were explored using a propensity score to account for confounding factors. Secondary endpoints included the impact of tumor expression of O6-methylguanine-methyltransferase (MGMT), alkylpurine-DNA-N-glycosylase (APNG), and carbonic anhydrase IX (CAIX), and progression-free survival (PFS). Among 116 patients, 58 received TACE (15 siNET and 43 panNET) and 58 received TAE (42 siNET and 16 panNET). TACE was associated with a higher ORR than TAE (43 vs 22%, P = 0.045), which remained statistically significant on propensity-adjusted multivariable analysis (OR 2.71, 95% CI: (1.08-7.17), P = 0.038). TACE provided longer PFS than TAE in panNET patients (12.9 vs 6.4 months, P = 0.026), but not in siNET patients (16.1 vs 15.1 months, P = 0.47). Low APNG expression was predictive of higher ORR with TACE (70 vs 16%, P < 0.001), while the expression of MGMT and CAIX had no impact. TACE-STZ provided a higher ORR than TAE, although it yielded longer PFS only in patients with panNET. Low tumor expression of APNG might help select the best candidates for TACE-STZ, although this result was only exploratory.

Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+ BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+ BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished tricarboxylic acid (TCA) glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine-resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and -resistant BC cells, which can be exploited for combinatorial therapy.