Endocrine-related cancer最新文献

Midgut neuroendocrine tumors (NET) derive from enterochromaffin cells, which have an close interrelationship with intestinal microbiota. Recently, we utilized 16S rRNA sequencing to uncover that midgut NET patients have a depleted gut microbiome and a specific fecal microbial signature. This study aims to validate these findings and to further characterize the role of microbes and microbial metabolic pathways in midgut NET patients with and without carcinoid syndrome (CS). Fecal samples from 60 midgut NET patients and 20 household-matched controls were subjected to whole metagenomics sequencing. We found that the gut microbial community composition of midgut NET patients differed from that of controls, with 2 genera, 17 species and 9 microbial pathways showing differential abundance (p < 0.001). No differences in microbial composition were observed between midgut NET patients with and without CS (p < 0.05). However, we did observe changes in inter-genus correlations of Bacteroides, Odoribacter, Parasutterella, Klebsielle, Ruminococcus and Proteobacteria when comparing these two patient groups. A signature of 16 microbial species (area under the receiver operating characteristic curve (AUROC) 0.892) or 18 microbial pathways (AUROC 0.909) accurately predicted the presence of a midgut NET. Furthermore, a microbial signature consisting of 14 functional microbial pathways distinguished CS patients from non-CS patients (AUROC 0.807). This study confirms that the gut microbiome of midgut NET patients is altered at the metagenomic level, which is not related to the presence of CS. A fecal microbial signature could constitute a novel biomarker for the diagnosis of midgut NET or CS.

Bone is a common and debilitating site for metastatic cancer cell expansion. Skeletal metastasis is a multistage process, with primary stages of circulating tumour cells, progressing to a dormant state in vasculature and bone marrow niches, followed by tumorigenic reactivation, proliferation, and finally bone destruction. The frequency of bone metastasis is reconciled in Paget's "seed and soil" hypothesis, where a conducive microenvironment (bone niche) is essential for cancer cell colonisation. Cancer cells can mimic bone cells (osteomimicry) and interact with the bone marrow's vascular architecture, utilising pathways akin to hematopoietic stem cell expansion. Current research suggests that each phase of bone metastasis is associated with specific gene expression and protein abundance patterns. For example, E-selectin, CXCR-4, and CXCL-12 are crucial for cancer cell homing, dormancy, and colonisation of bone tissue. In contrast, different primary cancers appear to have unique staging profiles. In prostate cancer, dormancy is modulated by the CXCR-4/CXCL-12, ANXA2/CXCL12, and GAS6 pathways, while in breast cancer, dormancy involves ERK1/2, p38, MSK1, LIF, BMP-7, TGF-β1/2, and bone resorption factors. Conversely, osteoblastic metastasis in both breast and prostate cancers is characterised by ET-1, Dkk1 suppression, and the release of IL-6, MCP-1, VEGF, FGF, and IGF, while osteolytic metastasis primarily depends on PTHrP, RANKL, OPG, TGF-β, IGF, TNF-α, IL-1, and IL-7. Understanding the complex molecular mechanisms facilitating cancer cell colonisation and expansion in bone tissues is essential for developing effective treatments to prevent bone metastases . In this review, we discuss current theories linking bone remodelling with bone.

Non-functioning pituitary adenomas (NFPAs) are a highly heterogeneous group and often shows invasion, but few studies have explored the invasion mechanism and biomarkers for specific subtypes. This study was designed to describe the role of HIF1α and its downstream genes in specific subtypes of NFPAs. Specimens were classified into two subtypes of NFPAs: 46 null cell adenomas (28 invasive, 18 non-invasive) and 46 oncocytomas (11 invasive, 35 non-invasive). HIF1α, TIMP1, MT6-MMP, ECAD and NCAD were detected by qRT-PCR, western blot or immunohistochemistry in tumor tissue. The transwell assay was performed to measure the effects of HIF1α on tumor cell invasion in GH3 and GT1-1 cells. TIMP1, MT6-MMP, ECAD and NCAD were detected by western blot in HIF1α overexpressed GT1-1 cells. HIF1α mRNA and protein level was significantly up-regulated in invasive pituitary null cell adenomas but not in invasive pituitary oncocytoma. The TIMP1 mRNA and protein level was significantly down-regulated and MT6-MMP mRNA and protein level was significantly up-regulated in invasive pituitary null cell adenomas. Meanwhile, there were no significant differences in epithelial-mesenchymal transition (EMT) markers, ECAD and NCAD, between invasive and non-invasive pituitary null cell adenomas. The overexpression of HIF1α promoted the invasive capability of pituitary adenoma cells in vitro. Regarding the molecular mechanism, HIF1α overexpression could down-regulated TIMP1 and up-regulated MT6-MMP expression levels but not affected EMT markers expression. Our results suggested HIF1α might contribute to the invasion of pituitary null cell adenomas through activating HIF1α/TIMP1/MT6-MMP pathway but not EMT.

The association between RET and multiple endocrine neoplasia type 2 was established in 1993 and remains one of the very few oncogenes for which distinct phenotypes (medullary thyroid cancer or phaeochromocytoma) are associated with the same hot-spot variants occurring either in germline or somatic DNA. Somatic RET fusion events have also been described in several cancers, including papillary thyroid cancer, non-small cell lung cancer, breast cancer, salivary gland cancer and pancreatic cancer. Highly selective RET inhibitors have improved outcomes in RET-altered cancers and have been well tolerated. Nevertheless, primary and acquired drug resistance has been observed, arising from distinct genomic alterations either in RET (on target resistance) or via alternate oncogenic pathways (bypass resistance). The same mechanisms of resistance have been observed across multiple cancer types, which implies RET-altered cancers evolve away from RET addiction via stochastic subclonal events. Understanding these mechanisms is crucial for identifying therapeutic opportunities to overcome resistance. Successful treatment targeting bypass oncogenes has been reported in several instances, at least for short-term outcomes; in contrast, although several compounds have been reported to overcome on-target RET alterations, none have yet been translated into routine clinical practice and this remains an area of urgent clinical need.

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy characterized by diagnostic challenges, high recurrence rates, and poor prognosis. This study explored the role of miRNA processing genes in ACC and their potential role as diagnostic and prognostic biomarkers. We analyzed the mRNA expression levels of miRNA machinery components (DROSHA, DGCR8, XPO5, RAN, DICER, TARBP2, and AGO2) utilizing mRNA-Seq data from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) projects. Additionally, protein levels were quantified in tissue samples from the Kolling Institute of Medical Research's tumor bank. Our results demonstrated that among all miRNA processing components, AGO2 exhibited significant overexpression in ACC compared to the normal adrenal cortex and benign adrenal adenoma (P < 0.001). Kaplan-Meier survival analysis indicated that higher AGO2 expression correlated with significantly worse overall survival in ACC patients (HR: 7.07, P < 0.001). Among 32 cancer types in TCGA, the prognostic significance of AGO2 was most prominent in ACC. This study is the first to report AGO2's potential as a diagnostic and prognostic biomarker in ACC, emphasizing its significance in ACC pathogenesis and potential application as a non-invasive liquid biopsy biomarker.

Differentiated thyroid cancer in older adults has been linked to alterations in the mutational landscape and tumor immune cell infiltration that create a tumor-permissive microenvironment. We sought to determine the impact of age on genomic alterations and immune cell composition in papillary thyroid cancer (PTC). Genomic alterations, immune cell composition, and clinical data were obtained using The Cancer Genome Atlas and computational immunogenomic analyses. Disease severity was recoded into three groups: Group A (T1-2N0M0), Group B (T1-3N1a-1bM0), and Group C (T4NxMx or TxNxM1). Histopathologic subtypes included conventional, follicular-variant, and tall cell variant PTC. Spearman's rank correlation, ANOVA, t-test, and multivariable linear regression were performed. A total of 470 PTC samples were retrieved from the TCGA portal with genomic alteration and immune cell composition data. TERT promoter alterations were more common in patients aged ≥65 years (26% vs 4%, P < 0.0001). Tumor mutational burden increased with increasing age (r = 0.463, P < 0.0001). Increasing age was associated with decreased CD8+ T cells (r = -0.15, P = 0.01) using CIBERSORT and decreased B cells (r = -0.13), CD8+ T cells (r = -0.19), and neutrophils (r = -0.14, P < 0.05) using TIMER. Multivariate regression found that increasing age was independently associated with increased resting NK cells and resting dendritic cells, and decreased naïve B cells and CD8+ T cells (P < 0.05). PTC tumors of older adults are characterized by increased TERT promoter alterations, increased tumor mutational burden, and a decreased cytotoxic CD8+ T cells and increased resting dendritic cell immune infiltrate. Further studies are needed to determine if these changes in immune cell infiltrate are associated with compromised outcomes.

Inhibiting the activity of the androgen receptor (AR) is the cornerstone treatment for advanced prostate cancer. AR-targeted therapies are highly effective in slowing disease progression but are not curative and the resultant disease state, termed castration-resistant prostate cancer, is associated with significant patient morbidity and mortality. In most cases, resistance to these therapies arises due to alterations that reactivate the AR signalling axis. Interestingly, it has long been recognised that potent activation of AR with supraphysiological levels of androgens can suppress prostate cancer growth in both preclinical models and patients. This intriguing paradox - where both inhibition and activation of AR have anti-cancer effects - is now being harnessed clinically in the form of bipolar androgen therapy (BAT). This review describes mechanisms underlying the tumour-suppressive functions of AR in the context of potent androgenic stimulation and discusses how our maturing understanding of these mechanisms is influencing the clinical deployment of BAT.

Liquid biopsies are a minimally invasive approach to obtain biomarkers including cell free DNA (cfDNA) from peripheral blood. Our study evaluated the utility of cfDNA in advanced thyroid cancers. Patients aged >18 years with metastatic medullary thyroid cancer (MTC), poorly differentiated thyroid cancer (PDTC), or anaplastic thyroid cancer (ATC) were enrolled in this prospective study between 2020 and 2024. As part of standard care, sequencing of germline and tumoral DNA was conducted, and patients with germline mutations were excluded from the study. Whole blood samples were collected in Streck cell-free DNA BCT tubes, cfDNA was extracted from plasma using the EZ1and2 ccfDNA kit and EZ2 Connect. The extracted cfDNA was then sequenced across 50 key cancer-related genes using the Oncomine Precision Assay (OPA) panel on an Ion Torrent Genexus Integrated Sequencer. Forty patients were included; 27 MTC, 2 ATC and 11 PDTC. Tumoral mutations were detected in 36 of the included patients (90%): cfDNA detected mutations in 18/36 patients (13 MTC, 1 ATC, 4 PDTC (50%). Sensitivity of cfDNA was 86% (6/7) pre TKI therapy, and reduced to 54% on therapy (13/24), suggestive of lack of tumor-derived DNA shedding with strong on-target treatment efficacy. Median cfDNA concentration was higher in samples with a detected mutation than those without, 11.91 ng/ml vs 5.81 ng/ml respectively. While an increasing cfDNA was associated with worse progression free survival (p < 0.01). cfDNA is a novel biomarker with potential to monitor disease progression in patients with advanced thyroid cancers.

Up to 30% of adrenocortical carcinoma (ACC) patients have metastasised disease upon initial presentation and systemic treatments currently fail to sufficiently improve survival. Palliative primary tumour resection can be considered for symptomatic relief, but its potential survival benefit remains a topic of debate. This systematic review therefore aims to assess the effect of primary tumour resection on overall survival in patients with metastatic ACC. A systematic review was performed using Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Relevant databases were searched from 2000-2024 for studies on primary tumour resection in metastatic ACC. Overall survival data were analysed. A total of thirteen studies on primary tumour resection for metastatic ACC were included. All studies were retrospective and assessed as having a high risk of bias. Data regarding adequate patient characteristics and indications for surgery were missing in all studies. Hence, current literature is hampered by both indication and selection bias to draw any conclusions on the survival benefit of primary tumour resection in patients with metastasised ACC. However, twelve out of thirteen studies (92%) demonstrated longer overall survival after primary tumour resection compared to no surgery. Whereas this is in line with retrospective data on other cancers, randomised controlled trials in other tumours, like breast and colorectal cancer, have failed to display survival benefits of primary tumour resection. These cancers are however relatively chemo-sensitive, unlike ACC. Primary tumour resection could therefore only be considered on individual patient basis.