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Vemurafenib activates the sonic hedgehog pathway and promotes thyroid cancer stem cell self-renewal. Vemurafenib激活声波hedgehog通路,促进甲状腺癌症干细胞自我更新。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-27 Print Date: 2023-11-01 DOI: 10.1530/ERC-22-0392
Yurong Lu, Yuqing Zhao, Penggang Liu, Xiulong Xu

B-Raf kinase inhibitors such as vemurafenib (PLX4032) and dabrafenib have limited therapeutic efficacy on BRAF-mutated thyroid cancer. Cancer stem cells (CSCs) play important roles in tumor recurrence, drug resistance, and metastasis. Whether CSCs play a role in dampening the antitumor activity of B-Raf kinase inhibitors remains unknown. Here, we report that vemurafenib (PLX4032) induced the expression of several stemness-related genes including Gli1, Snail, BMI1, and SOX2 in two anaplastic thyroid cancer cell lines, SW1736 and 8505C, but decreased the expression of these genes in A375 cells, a human melanoma cell line. PLX4032 promoted thyroid cancer stem cell self-renewal, as evidenced by increased numbers of aldehyde dehydrogenase-positive cells and thyrospheres. Mechanistically, PLX4032 activates the PI-3 and mitogen-activated protein kinase pathways through HER3 to cross-activate Gli1, a transcription factor of the sonic hedgehog (Shh) pathway. GANT61, a specific inhibitor of Gli1, blocked the expression of the stemness-related genes in PLX4032-treated thyroid cancer cells in vitro and in vivo in two thyroid cancer xenograft models. GANT61 treatment alone weakly inhibited SW1736 tumor growth but enhanced the antitumor activity of PLX4032 when used in combination. Our study provides mechanistic insights into how thyroid cancer poorly responds to B-Raf kinase inhibitors and suggests that targeting B-Raf and the Shh pathway in combination may overcome thyroid cancer drug resistance.

B-Raf激酶抑制剂,如vemurafenib(PLX4032)和dabrafenib对BRAF突变的甲状腺癌症的治疗效果有限。癌症干细胞(CSCs)在肿瘤复发、耐药和转移中起着重要作用。CSC是否在抑制B-Raf激酶抑制剂的抗肿瘤活性中发挥作用尚不清楚。在此,我们报道了vemurafenib(PLX4032)在两种间变性甲状腺癌症细胞系SW1736和8505C中诱导了包括Gli1、Snail、BMI1和SOX2在内的几种干细胞相关基因的表达,但在A375细胞(一种人类黑色素瘤细胞系)中降低了这些基因的表达。PLX4032促进了甲状腺癌症干细胞的自我更新,醛脱氢酶阳性细胞和甲状腺球数量的增加证明了这一点。从机制上讲,PLX4032通过HER3激活PI-3和促分裂原活化蛋白激酶途径,以交叉激活Gli1,一种声音刺猬(Shh)途径的转录因子。GANT61是Gli1的特异性抑制剂,在两种甲状腺癌症异种移植模型中,在体外和体内阻断PLX4032治疗的甲状腺癌症细胞中干细胞相关基因的表达。单独的GANT61治疗弱地抑制SW1736肿瘤生长,但当联合使用时增强了PLX4032的抗肿瘤活性。我们的研究为癌症对B-Raf激酶抑制剂的不良反应提供了机制上的见解,并表明联合靶向B-Raf和Shh途径可以克服甲状腺癌症耐药性。
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引用次数: 0
Embryonic stem cell factor FOXD3 (Genesis) defects in gastrointestinal stromal tumors. 胃肠道间质瘤中的胚胎干细胞因子FOXD3(Genesis)缺陷。
IF 4.1 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-11 Print Date: 2023-10-01 DOI: 10.1530/ERC-23-0067
Fabio R Faucz, Anelia D Horvath, Guillaume Assié, Madson Q Almeida, Eva Szarek, Sosipatros Boikos, Anna Angelousi, Isaac Levy, Andrea G Maria, Ajay Chitnis, Cristina R Antonescu, Rainer Claus, Jérôme Bertherat, Christoph Plass, Charis Eng, Constantine A Stratakis

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as 'Genesis' and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

胃肠道间质瘤(GISTs)是间充质肿瘤,据信起源于Cajal(ICC)的间质细胞,通常由酪氨酸激酶受体(TKR)KIT或PDGFRA的过度表达引起。在这里,我们提出的证据表明,胚胎干细胞因子FOXD3,首次被鉴定为“Genesis”,参与胃肠道和神经嵴细胞的发育,与GIST的发病机制有关;在体外和斑马鱼以及FOXD3缺乏的小鼠模型中对其参与进行了研究。来自58名野生型GIST患者的样本用于分子分析,包括Sanger测序、比较基因组杂交和甲基化分析。免疫组织化学和蛋白质印迹评价用于评估FOXD3的表达。此外,我们在组织样本和转染细胞中进行了体外功能研究,以确认已鉴定的遗传变异的致病性。在分离的GIST患者中发现了种系部分失活的FOXD3序列变体(p.R54H和p.Ala88_Gly91del)。1p染色体缺失是肿瘤中最常见的染色体异常。体外实验证明FOXD3在这些变体存在的情况下受损。动物研究显示胃肠道神经网络被破坏,ICC的数量和分布也发生了变化。FOXD3抑制人细胞中KIT的表达;其失活导致斑马鱼和小鼠的ICC增加,为FOXD3缺陷和KIT过表达导致GIST形成之间的功能联系提供了证据。
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引用次数: 0
Intratumour microbiota modulates adrenocortical cancer responsiveness to mitotane. 肿瘤内微生物群调节癌症肾上腺皮质对米托坦的反应。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-11 Print Date: 2023-10-01 DOI: 10.1530/ERC-23-0094
Giulia Cantini, Elena Niccolai, Letizia Canu, Leandro Di Gloria, Simone Baldi, Arianna Pia Propato, Laura Fei, Giulia Nannini, Soraya Puglisi, Gabriella Nesi, Matteo Ramazzotti, Amedeo Amedei, Michaela Luconi
The infiltrating microbiota represents a novel cellular component of the solid tumour microenvironment that can influence tumour progression and response to therapy. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy for which mitotane (MTT) treatment represents the first-line therapy, though its efficacy is limited to a therapeutic window level (14–20 mg/L). Novel markers able to predict those patients who would benefit from MTT therapy are urgently needed to improve patient’s management. The aim of our study was to evaluate the presence of intratumoural bacterial microbiota DNA in 26 human ACC tissues vs 9 healthy adrenals; moreover, the association between the relative bacterial composition profile, the tumour mass characteristics and MTT ability to reach high circulating levels in the early phase of treatment, were explored. We found the presence of bacterial DNA in all adrenal samples from both tumours and healthy cortex specimens, documenting significant differences in the microbial composition between malignancy and normal adrenals: in detail, the ACC tissues were characterised by a higher abundance of the Proteobacteria phylum (especially the Pseudomonas and Serratia genera). In addition, the Proteobacteria’s low abundance was negatively associated with tumour size, Ki67 and cortisol secretion. MTT levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.
浸润微生物群代表了实体瘤微环境中一种新的细胞成分,可以影响肿瘤的进展和对治疗的反应。肾上腺皮质癌(ACC)是一种罕见的侵袭性内分泌恶性肿瘤,尽管其疗效仅限于治疗窗口水平(14-20mg/L),但MTT治疗是其一线治疗方法。迫切需要能够预测那些将从MTT治疗中受益的患者的新标志物来改善患者的管理。我们研究的目的是评估26个人类ACC组织与9个健康肾上腺中肿瘤内细菌微生物群DNA的存在;此外,还探讨了相对细菌组成、肿瘤质量特征和MTT在治疗早期达到高循环水平的能力之间的关系。我们在肿瘤和健康皮质标本的所有肾上腺样本中都发现了细菌DNA,记录了恶性肿瘤和正常肾上腺之间微生物组成的显著差异:详细而言,ACC组织的特征是变形菌门(尤其是假单胞菌属和沙雷氏菌属)的丰度更高。此外,变形杆菌的低丰度与肿瘤大小、Ki67和皮质醇分泌呈负相关。在变形杆菌、假单胞菌和沙雷氏菌丰度高、拟杆菌门、厚壁菌门和链球菌丰度低的ACC患者中,MTT水平在9个月时达到较高水平。这些发现首次表明,人类ACC以浸润细菌为特征,其特定丰度似乎会影响9个月时循环MTT水平的增加。
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引用次数: 0
GH and IGF1 in cancer therapy resistance. 生长激素和IGF1在肿瘤治疗耐药中的作用。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-22-0414
Reetobrata Basu, John Kopchick

Despite landmark advances in cancer treatments over the last 20 years, cancer remains the second highest cause of death worldwide, much ascribed to intrinsic and acquired resistance to the available therapeutic options. In this review, we address this impending issue, by focusing the spotlight on the rapidly emerging role of growth hormone action mediated by two intimately related tumoral growth factors - growth hormone (GH) and insulin-like growth factor 1 (IGF1). Here, we not only catalog the scientific evidences relating specifically to cancer therapy resistance inflicted by GH and IGF1 but also discuss the pitfalls, merits, outstanding questions and the future need of exploiting GH-IGF1 inhibition to tackle cancer treatment successfully.

尽管过去20年来癌症治疗取得了里程碑式的进展,但癌症仍然是全世界第二大死亡原因,这在很大程度上归因于对现有治疗方案的内在和获得性耐药性。在这篇综述中,我们通过关注生长激素在两种密切相关的肿瘤生长因子-生长激素(GH)和胰岛素样生长因子1 (IGF1)介导的生长激素作用中迅速出现的作用来解决这一迫在眉睫的问题。在这里,我们不仅列出了与GH和IGF1引起的癌症治疗耐药相关的科学证据,还讨论了利用GH-IGF1抑制成功解决癌症治疗的缺陷、优点、悬而未决的问题和未来的需要。
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引用次数: 0
Chromosomal alterations in sporadic medullary thyroid carcinoma and correlation with outcome. 散发性甲状腺髓样癌的染色体改变及其与预后的关系。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-22-0251
Teresa Ramone, Cristina Romei, Raffaele Ciampi, Roberta Casalini, Angelo Valetto, Veronica Bertini, Francesco Raimondi, Anthony Onoja, Alessandro Prete, Antonio Matrone, Carla Gambale, Paolo Piaggi, Liborio Torregrossa, Clara Ugolini, Rossella Elisei

Somatic copy number alterations (SCNA) involving either a whole chromosome or just one of the arms, or even smaller parts, have been described in about 88% of human tumors. This study investigated the SCNA profile in 40 well-characterized sporadic medullary thyroid carcinomas by comparative genomic hybridization array. We found that 26/40 (65%) cases had at least one SCNA. The prevalence of SCNA, and in particular of chromosome 3 and 10, was significantly higher in cases with a RET somatic mutation. Similarly, SCNA of chromosomes 3, 9, 10 and 16 were more frequent in cases with a worse outcome and an advanced disease. By the pathway enrichment analysis, we found a mutually exclusive distribution of biological pathways in metastatic, biochemically persistent and cured patients. In particular, we found gain of regions involved in the intracellular signaling and loss of regions involved in DNA repair and TP53 pathways in the group of metastatic patients. Gain of regions involved in the cell cycle and senescence were observed in patients with biochemical disease. Finally, gain of regions associated with the immune system and loss of regions involved in the apoptosis pathway were observed in cured patients suggesting a role of specific SCNA and corresponding altered pathways in the outcome of sporadic MTC.

体细胞拷贝数改变(SCNA)涉及整个染色体或仅一条臂,甚至更小的部分,已经在大约88%的人类肿瘤中被描述。本研究利用比较基因组杂交技术对40例散发性甲状腺髓样癌的SCNA谱进行了研究。我们发现26/40(65%)的病例至少有一个SCNA。在RET体细胞突变的病例中,SCNA的患病率,特别是3号和10号染色体的患病率明显更高。同样,3、9、10和16号染色体的SCNA在预后较差和疾病晚期的病例中更常见。通过通路富集分析,我们发现在转移性、生化持久性和治愈患者中存在相互排斥的生物通路分布。特别是,我们发现在转移患者组中,参与细胞内信号传导的区域增加,参与DNA修复和TP53通路的区域减少。在生化疾病患者中观察到参与细胞周期和衰老的区域增加。最后,在治愈患者中观察到与免疫系统相关的区域的增加和与凋亡通路相关的区域的丧失,这表明特异性SCNA和相应的通路改变在散发性MTC的结果中起作用。
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引用次数: 0
Targeting growth hormone in cancer: future perspectives. 靶向生长激素治疗癌症:未来展望。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-23-0033
Yue Wang, Stephen M F Jamieson, Jo K Perry

Decades of published research support a role for growth hormone (GH) in cancer. Accordingly, there is increasing interest in targeting GH in oncology, with GH antagonists exhibiting efficacy in xenograft studies as single agents and in combination with anticancer therapy or radiation. Here we discuss challenges associated with using growth hormone receptor (GHR) antagonists in preclinical models and considerations for translation, such as the identification of predictive biomarkers for selecting patients and for monitoring drug efficacy. Ongoing research will determine whether suppressing GH signalling pharmacologically will also reduce the risk of developing cancer. An increase in GH-targeted drugs in preclinical development will ultimately provide new tools to test anticancer efficacy of blocking the GH signalling pathway.

几十年发表的研究支持生长激素(GH)在癌症中的作用。因此,人们对肿瘤靶向生长激素越来越感兴趣,生长激素拮抗剂在异种移植研究中作为单一药物或与抗癌治疗或放疗联合使用显示出疗效。在这里,我们讨论了在临床前模型中使用生长激素受体(GHR)拮抗剂所面临的挑战,以及对翻译的考虑,例如确定用于选择患者和监测药物疗效的预测性生物标志物。正在进行的研究将确定从药理学上抑制生长激素信号是否也会降低患癌症的风险。GH靶向药物临床前开发的增加将最终为测试阻断GH信号通路的抗癌功效提供新的工具。
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引用次数: 1
Congenital IGF-1 deficiency protects from cancer: lessons from Laron syndrome. 先天性IGF-1缺乏可以预防癌症:从Laron综合征的经验教训。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-22-0394
Zvi Laron, Haim Werner

Many clinical and experimental studies have implicated the growth hormone (GH)-insulin-like growth factor (IGF-1) axis with the progression of cancer. The epidemiological finding that patients with Laron syndrome (LS), the best-characterized disease under the spectrum of congenital IGF-1 deficiencies, do not develop cancer is of major scientific and translational relevance. The evasion of LS patients from cancer emphasizes the central role of the GH-IGF-1 system in cancer biology. To identify genes that are differentially expressed in LS and that might provide a biological foundation for cancer protection, we have recently conducted genome-wide profiling of LS patients and normal controls. Analyses were performed on immortalized lymphoblastoid cell lines derived from individual patients. Bioinformatic analyses identified a series of genes that are either over- or under-represented in LS. Differential expression was demonstrated in a number of gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT and PI3K-AKT signaling, etc. Major differences between LS and controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. The identification of novel downstream targets of the GH-IGF-1 network highlights the biological complexity of this hormonal system and sheds light on previously unrecognized mechanistic aspects associated with GH-IGF-1 action in the cancer cell.

许多临床和实验研究表明,生长激素(GH)-胰岛素样生长因子(IGF-1)轴与癌症的进展有关。Laron综合征(LS)是先天性IGF-1缺乏症谱系中最具特征的疾病,其患者不发展为癌症,这一流行病学发现具有重大的科学和转化意义。LS患者对癌症的逃避强调了GH-IGF-1系统在癌症生物学中的核心作用。为了确定LS中差异表达的基因,并可能为癌症保护提供生物学基础,我们最近对LS患者和正常对照进行了全基因组分析。对来自个体患者的永生化淋巴母细胞样细胞系进行了分析。生物信息学分析确定了一系列在LS中表现过度或不足的基因。在细胞周期、代谢控制、细胞因子-细胞因子受体相互作用、Jak-STAT和PI3K-AKT信号传导等多个基因家族中均存在差异表达。LS与对照组在细胞周期分布、凋亡和自噬相关的通路上也存在主要差异。GH-IGF-1网络的新下游靶点的鉴定突出了这一激素系统的生物学复杂性,并揭示了以前未被认识的与GH-IGF-1在癌细胞中的作用相关的机制方面。
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引用次数: 1
One hundred years after the discovery of insulin and glucagon: the history of tumors and hyperplasias that hypersecrete these hormones. 胰岛素和胰高血糖素发现一百年后:肿瘤和增生过度分泌这些激素的历史。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-23-0046
Wouter W de Herder, Gunter Klöppel

One century ago, in 1922, Frederick G Banting, Charles H Best, James B Collip and John J R Macleod first published their experiments resulting in the isolation of a hypoglycemic factor, named insulin, from a solution extract from a dog's pancreas. One year later, in 1923, a hyperglycemic factor named glucagon was isolated by Charles P Kimball and John R Murlin. In the following years, it could be demonstrated that pancreatic islet alpha- and beta-cell neoplasms and hyperplasias could inappropriately secrete excessive amounts of these two hormones. This review is a sequel to the discovery of insulin and glucagon and introduces the history of this fascinating group of neuroendocrine neoplasms and hyperplasias of the pancreas.

一个世纪前的1922年,弗雷德里克·G·班廷、查尔斯·H·贝斯特、詹姆斯·B·科利普和约翰·J·R·麦克劳德首次发表了他们的实验成果,从狗的胰腺提取液中分离出一种名为胰岛素的降血糖因子。一年后,也就是1923年,查尔斯·P·金博尔和约翰·R·穆林分离出了一种名为胰高血糖素的高血糖因子。在接下来的几年里,可以证明胰岛α细胞和β细胞肿瘤和增生可以不适当地分泌过量的这两种激素。这篇综述是继胰岛素和胰高血糖素的发现,并介绍了这组迷人的神经内分泌肿瘤和胰腺增生的历史。
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引用次数: 0
Whole-exome sequencing of rectal neuroendocrine tumors. 直肠神经内分泌肿瘤的全外显子组测序。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-01 DOI: 10.1530/ERC-22-0257
Yuanliang Li, Yiying Guo, Zixuan Cheng, Chao Tian, Yingying Chen, Ruao Chen, Fuhuan Yu, Yanfen Shi, Fei Su, Shuhua Zhao, Zhizheng Wang, Jie Luo, Huangying Tan

The genetic characteristics of rectal neuroendocrine tumors (R-NETs) were poorly understood. Depicting the genetic characteristics may provide a biological basis for prognosis prediction and novel treatment development. Tissues of 18 R-NET patients were analyzed using whole-exome sequencing. The median tumor mutation burden (TMB) and microsatellite instability (MSI) were 1.15 Muts/MB (range, 0.03-23.28) and 0.36 (range, 0.00-10.97), respectively. Genes involved in P53 signaling, PI3K-AKT signaling, DNA damage repair, WNT signaling, etc. were frequently altered. Higher TMB (P = 0.078), higher CNV (P = 0.110), somatic mutation of CCDC168 (P = 0.049), HMCN1 (P = 0.040), MYO10 (P = 0.007), and amplification of ZC3H13 (P < 0.001) were associated with shorter OS. Potentially targetable gene alterations (PTGAs) were seen in 72% of the patients. FGFR1 amplification (22%) was the most common PTGA followed by BARD1 and BRCA2 mutation (each 17%). As for gene variations associated with the efficacy of immune checkpoint blockade (ICB), FAT1 alteration (39%) and PTEN depletion (28%) were commonly observed. In conclusion, frequently altered oncogenic pathways might contribute to the development and progression of R-NETs. Gene alterations significantly associated with prognosis might be potential novel targets. Targeted therapy might be a promising strategy as targetable alterations were prevalent in R-NETs. FAT1 alteration and PTEN depletion might be the main genetic alterations influencing the response to ICB besides overall low TMB and MSI in R-NETs.

直肠神经内分泌肿瘤(R-NETs)的遗传特征尚不清楚。描述遗传特征可以为预后预测和新的治疗开发提供生物学基础。采用全外显子组测序对18例R-NET患者的组织进行分析。中位肿瘤突变负荷(TMB)和微卫星不稳定性(MSI)分别为1.15 Muts/MB(范围0.03 ~ 23.28)和0.36 Muts/MB(范围0.00 ~ 10.97)。参与P53信号、PI3K-AKT信号、DNA损伤修复、WNT信号等的基因频繁改变。较高的TMB (P = 0.078)、较高的CNV (P = 0.110)、CCDC168体细胞突变(P = 0.049)、HMCN1 (P = 0.040)、MYO10 (P = 0.007)和ZC3H13扩增(P < 0.001)与较短的生存期相关。72%的患者出现潜在靶向基因改变(PTGAs)。FGFR1扩增(22%)是最常见的PTGA,其次是BARD1和BRCA2突变(各17%)。至于与免疫检查点阻断(ICB)疗效相关的基因变异,常见的是FAT1改变(39%)和PTEN耗竭(28%)。总之,经常改变的致癌途径可能有助于R-NETs的发生和发展。与预后显著相关的基因改变可能是潜在的新靶点。靶向治疗可能是一种很有前途的策略,因为可靶向改变在R-NETs中很普遍。FAT1改变和PTEN缺失可能是影响R-NETs对ICB反应的主要遗传改变,除了总体低TMB和MSI。
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引用次数: 2
The aggressiveness of succinate dehydrogenase subunit B-deficient chromaffin cells is reduced when their bioelectrical properties are restored by glibenclamide. 当格列本脲恢复琥珀酸脱氢酶亚基B缺陷嗜铬细胞的生物电特性时,其攻击性降低。
IF 3.9 2区 医学 Q2 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-08-25 Print Date: 2023-10-01 DOI: 10.1530/ERC-23-0167
Francesca Amore, Rachele Garella, Alice Santi, Daniele Guasti, Serena Martinelli, Letizia Canu, Daniele Bani, Jiri Neuzil, Mario Maggi, Roberta Squecco, Elena Rapizzi

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumours, mostly resulting from mutations in predisposing genes. Mutations of succinate dehydrogenase (SDH) subunit B (SDHB) are associated with high probability of metastatic disease. Since bioelectrical properties and signalling in cancer are an emerging field, we investigated the metabolic, functional and electrophysiological characteristics in human succinate dehydrogenase subunit B (SDHB)-deficient pheochromocytoma cells. These cells exhibited reduced SDH function with elevated succinate-to-fumarate ratio and reduced intracellular ATP levels. The analysis of membrane passive properties revealed a more hyperpolarized membrane potential and a lower cell capacitance of SDHB-deficient cells compared to the parental ones. These bioelectrical changes were associated with reduced proliferation and adhesion capacity of SDHB-deficient cells. Only in SDHB-deficient cells, we also observed an increased amplitude of potassium currents suggesting an activation of ATP-sensitive potassium channels (KATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific KATP inhibitor, or to ATP caused normalization of potassium current features and altered proliferation and adhesion. In this work, we show for the first time that reduced intracellular ATP levels in SDHB-deficient chromaffin cells impaired cell bioelectrical properties, which, in turn, are associated with an increased cell aggressiveness. Moreover, we first ever demonstrated that glibenclamide not only reduced the outward potassium currents in SDHB-deficient cells but increased their growth capacity, reduced their ability to migrate and shifted their phenotype towards one more similar to that of parental one.

嗜铬细胞瘤/副神经节瘤(PPGLs)是一种神经内分泌肿瘤,主要由易感基因突变引起。琥珀酸脱氢酶(SDH)亚单位B(SDHB)的突变与转移性疾病的高概率有关。由于癌症的生物电特性和信号传导是一个新兴领域,我们研究了人琥珀酸脱氢酶B亚基(SDHB)缺陷型嗜铬细胞瘤细胞的代谢、功能和电生理特征。这些细胞表现出SDH功能降低,琥珀酸盐与富马酸盐的比例升高,细胞内ATP水平降低。膜被动特性的分析显示,与亲代细胞相比,SDHB缺陷细胞的膜电位更超极化,细胞电容更低。这些生物电变化与SDHB缺陷细胞的增殖和粘附能力降低有关。仅在SDHB缺乏的细胞中,我们还观察到钾电流幅度增加,表明ATP敏感性钾通道(KATP)激活。事实上,SDHB缺陷细胞暴露于特异性KATP抑制剂格列本脲或ATP导致钾电流特征正常化,并改变增殖和粘附。在这项工作中,我们首次表明,SDHB缺陷的嗜铬细胞中细胞内ATP水平的降低损害了细胞的生物电特性,而这反过来又与细胞攻击性的增加有关。此外,我们首次证明,格列本脲不仅减少了SDHB缺陷细胞的外向钾电流,而且增加了它们的生长能力,降低了它们的迁移能力,并使它们的表型向更类似于亲本的表型转变。
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引用次数: 0
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Endocrine-related cancer
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