胰高糖素样肽-1受体激动剂对甲状腺乳头状癌细胞生长和增殖的影响

目的:探讨甲状腺癌细胞中胰高糖素样肽-1（Glucagon like peptide-1,GLP-1）受体的表达情况,及其对癌细胞生长和增殖的影响。方法:Western blot法检测甲状腺乳头状癌（Papillary thyroid cancer,PTC）细胞系GLP-1受体表达情况。采用四甲基偶氮唑蓝法（MTT）评价两种GLP-1受体激动剂艾塞那肽和利拉鲁肽处理后细胞增殖情况。Western blot法测定细胞中蛋白激酶B（Protein kinase B,Akt）及细胞外信号调节蛋白激酶1/2（Extracellular signal-regulated kinase 1/2,Erk1/2）等细胞信号通路相关蛋白的表达。结果:PTC细胞系BCPAP、TPC-1中均可检测到GLP-1受体的表达。艾塞那肽和利拉鲁肽分别以1nmol/L、10noml/L和100nmol/L作用于细胞24h、48h和72h后,实验组细胞增殖率与对照组相比无统计学差异。不同浓度艾塞那肽和利拉鲁肽作用细胞24h后,实验组Akt和Erk蛋白表达水平及其磷酸化程度与对照组相比无统计学差异。结论:人甲状腺乳头状癌细胞中有GLP-1受体的表达。但是,GLP-1受体激动剂对甲状腺癌细胞的增殖无明显促进作用。同时,GLP-1受体激动剂对与细胞增殖密切相关的Akt和Erk通路无明显作用。     

人甲状腺髓样癌细胞株的研究进展

甲状腺髓样癌是常见的头颈部恶性肿瘤,也是近年来发病率增加最快的恶性肿瘤之一,近年来对其基础研究较为关注。本文复习有关文献,对已建株的人甲状腺髓样癌细胞株(TT细胞株)的特性及研究进展全面总结,以期对临床及药物的研发提供帮助。     

遗传型甲状腺髓样癌1例分析

甲状腺髓样癌(MTC)是中等恶性程度的内分泌肿瘤,其恶性程度高于甲状腺乳头状腺癌(PTC)和甲状腺滤泡状腺癌(FTC),但发病率低于二者。本病例提示我们如有双侧甲状腺肿物的患者需要询问其家族史,注意有无遗传性MTC情况。     

58例甲状腺髓样癌降钙素及其基因相关肽检测的临床意义

目的:探讨甲状腺髓样癌患者降钙素及其基因相关肽的变化规律以指导临床治疗方案的选择和患者预后的判断.方法:对58例甲状腺髓样癌患者血清中降钙素进行分析及应用免疫组织化学方法观察相应标本中降钙素及其基因相关肽的表达情况;对新入组患者进行放射免疫学测定.结果:1)术前降钙素水平正常与升高的患者之间,颈淋巴结转移存在显著性差异(P＜0.01).2)术后1个月降钙素水平正常与升高的患者之间,肿瘤复发存在显著性差异(P＜0.01).3)约98%的患者肿瘤标本降钙素染色呈阳性,而降钙素基因相关肽的阳性率为87.8%.4)部分术前降钙素水平正常的惠者降钙素基因相关肽水平升高.5)术后1周左右降钙素下降至一稳定水平.结论:降钙素可以作为指导甲状腺髓样癌诊断和治疗的重要指标,检测降钙素基因相关肽有助于部分降钙素阴性的甲状腺髓样癌患者术前诊断.     

REGγ基因沉默对甲状腺髓样癌细胞凋亡的影响*

目的：研究小干扰RNA（smallinterferingRNA ,siRNA ）方法抑制蛋白酶体激活剂REGγ的基因表达对人甲状腺髓样癌TT细胞株凋亡的影响。方法：培养人甲状腺髓样癌TT细胞株,构建真核表达载体pREGγ-shRNA 及阴性对照质粒pNeg-shRNA,在脂质体Lipofectamine 2000的介导下转染人甲状腺髓样癌TT细胞株,采用RT-PCR
和WesternBlot法检测pREGγ-shRNA 转染和pNeg-shRNA 转染的TT细胞之间REGγmRNA及REGγ蛋白质表达之间的差别;然后采用TUNEL法检测REGγshRNA 转染和阴性质粒转染的TT细胞的凋亡率之间的差别,以及WesternBlot法检测pREGγ-shRNA 转染和pNeg-shRNA 转染的TT细胞凋亡因子Caspase- 3 表达之间的差别。结果：真核表达载体pREGγ-shRNA 转染TT细胞的REGγmRNA和REGγ蛋白表达水平明显低于pNeg-shRNA 转染的TT细胞（P<0.05）,pREGγ-shRNA 转染的TT细胞的凋亡水平明显高于pNeg-shRNA 转染的TT细胞（P<0.05）。 结论：应用siRNA 技术能有效的抑制人甲状腺髓样癌细胞REGγ基因的表达,抑制蛋白酶体激活剂REGγ基因的表达能明显地促进TT细胞的凋亡,提示REGγ可阻止细胞凋亡。REGγ在人甲状腺髓样癌细胞凋亡中的地位,为肿瘤的生物学治疗提供了新的思路。     

胰高血糖素样肽-1受体激动剂与肿瘤相关性的研究进展

我国糖尿病和肿瘤防治工作均面临着严峻挑战。有研究显示2型糖尿病患者与普通患者相比有更高的肿瘤发病率。胰高血糖素样肽-1（glucagon-like peptide-1,GLP-1）受体激动剂因其减轻体重、保护胰岛β细胞、心血管获益以及副作用小等特点广泛用于2型糖尿病治疗。人体多个组织和器官均表达GLP-1受体,因此GLP-1受体激动剂在糖尿病患者中广泛应用对各肿瘤的发生、发展和转归备受关注,本文就GLP-1受体激动剂与各肿瘤的相互关系作一综述。     

甲状腺髓样癌的放射治疗新进展

甲状腺髓样癌（MTC）是一种源自甲状腺滤泡旁C细胞的神经内分泌肿瘤。 甲状腺髓样癌的初始治疗通常是手术。临床分期较晚的患者,尽管进行了积极的手术治疗,但局部复发风险仍很高。随着辐射技术的改进,足够的放疗剂量可以有效地照射到高危区域,同时最小化周围关键组织结构的受照剂量。因此放射治疗应该是局部晚期甲状腺髓样癌的治疗选择,以提高局部区域控制。     

甲状腺髓样癌的预后因素分析

目的　评估影响甲状腺髓样癌预后的因素。方法　采用统计学单、多因素分析研究本院初治 5 3例甲状腺髓样癌的预后因素。结果　总的 5年、10年、15年生存率各自为 6 6 %、5 9.9%和 5 3.2 %。单因素分析示 :原发灶累及双侧 ,原发灶 >4cm ,病灶外侵甲状腺包膜 ,无腹泻症状 ,远处转移 ,手术彻底程度影响预后。多因素示 :手术彻底程度是影响甲状腺髓样癌生存的独立预后因素。结论　手术彻底程度是影响甲状腺髓样癌生存的独立预后因素。     

甲状腺髓样癌的预后影响因素--73例临床分析

目的 探讨影响甲状腺髓样癌(MTC)预后的因素。方法：回顾性分析73例MTC手术治疗、术后放疗的临床和随访资料。结果：73例MTC中37例发生于30～40岁，女性多发，临床Ⅱ，Ⅲ期病例占到83．6％；根据有无颈部淋巴结肿大行癌灶局部广泛切除或甲状腺癌联合根治术，切除不满意者辅以术后放疗。治疗后I期病例五年生存率达100％，Ⅲ期为41．5％，Ⅳ期为零。8例姑息性切除辅以放疗者无l例生存达到5年：结论：临床分期和癌灶及其转移淋巴结切除的彻底性是影响MTC预后的重要因素。肿物巨大而累及较广泛者，因有不完整的包膜而常能被完全切除，即使有少量癌灶残留，术后辅以放疗，也可取得较好的疗效，而不应轻易放弃手术治疗：     

二甲双胍对人滤泡状甲状腺癌细胞生长和能量代谢的影响

目的:观察不同浓度二甲双胍对人滤泡状甲状腺癌(follicular thyroid cancer,FTC）细胞增殖、凋亡及能量代谢的影响。方法:体外培养人FTC细胞(FTC-133),分为对照组和不同浓度二甲双胍处理组（1、3和10mmol/L）,分别培养24h、48h和72h。四甲基偶氮唑蓝（MTT）法检测细胞增殖,Annexin V-FITC/PI流式细胞术检测细胞凋亡,Seahorse能量代谢分析仪检测细胞糖酵解及线粒体呼吸的变化。结果:与对照组相比,二甲双胍抑制FTC-133增殖,随浓度及处理时间的增加,抑制效应加大,呈剂量-时间依赖性（P＜0.05）。二甲双胍诱导FTC-133凋亡,随浓度及处理时间的增加,其中晚期凋亡率明显增加,呈剂量-时间依赖性（P＜0.05）。二甲双胍可影响FTC-133糖代谢,与对照组相比,随二甲双胍浓度增加,糖酵解和线粒体呼吸可明显抑制,呈剂量-时间依赖性（P＜0.05）。结论:二甲双胍抑制FTC-133增殖并诱导凋亡,其机制可能是影响癌细胞能量代谢进而抑制其能量供应。     

二甲双胍对甲状腺未分化癌细胞增殖和能量代谢的影响

目的:探讨二甲双胍对甲状腺未分化癌（anaplastic thyroid cancer,ATC）细胞增殖及能量代谢的影响,并检测糖酵解途径相关蛋白GLUT1、PKM2、LDHA表达的变化。方法:体外培养人ATC细胞和人正常甲状腺细胞,分为对照组和不同浓度二甲双胍（1、5、10mmol/L）处理组,并分别培养24h、48h。四甲基偶氮唑蓝（MTT）法检测细胞增殖,Seahorse能量代谢分析仪检测细胞糖酵解及线粒体呼吸的变化。Western blot检测各组细胞GLUT1、PKM2和LDHA蛋白表达变化。结果:与对照组相比,二甲双胍可抑制ATC细胞增殖,且呈剂量-时间依赖性（P<0.05）。二甲双胍可改变ATC细胞能量代谢模式,随二甲双胍处理浓度增加和时间延长,糖酵解和线粒体呼吸水平均可出现抑制,呈剂量-时间依赖性（P<0.05）。GLUT1、PKM2和LDHA在ATC细胞中过表达,而二甲双胍对ATC细胞中GLUT1、PKM2和LDHA蛋白的表达无明显影响。结论:二甲双胍可抑制ATC细胞增殖和能量代谢,但其机制仍有待于进一步研究。     

Current management of medullary thyroid cancer

Medullary thyroid cancer accounts for 5%-10% of all thyroid cancers. The majority of medullary thyroid cancers are sporadic, but 20% of cases are a result of a germline mutation in the ret proto-oncogene. Hereditary medullary thyroid cancer can be seen as part of the multiple endocrine neoplasia syndrome type 2A or 2B or as part of familial medullary thyroid cancer. This article discusses the current methods available for the diagnosis and evaluation of a patient with suspected medullary thyroid cancer. The management of medullary thyroid cancer is predominantly surgical excision, consisting of a total thyroidectomy and lymph node dissection. The extent and timing of surgical excision are discussed. Systemic therapeutic options are limited for medullary thyroid cancer, but several therapeutic targets show promise for the development of new therapies in the future.     

Systemic treatment and management approaches for medullary thyroid cancer

Although rare, medullary thyroid cancer (MTC) exemplifies the value that ever-expanding knowledge of molecular pathways and mechanisms brings to managing challenging cancers. Although surgery can be curative for MTC in many patients, a substantial proportion of patients present with locoregional or distant metastatic disease. Once distant disease occurs, treatment options are limited, and conventional cancer treatments such as cytotoxic chemotherapy are of minimal benefit. Biomarkers such as calcitonin and carcinoembryonic antigen are important correlates of disease burden as well as predictors of disease progress, including recurrence and survival. MTC is either sporadic (∼75%) or inherited (∼25%) as an autosomal dominant disease. Regardless, germline and somatic mutations, particularly in the rearranged during transfection (RET) proto-oncogene, are key factors in the neoplastic process. Gain-of-function RET mutations result in overactive proteins that lead to abnormal activation of downstream signal transduction pathways, resulting in ligand-independent growth and resistance to apoptotic stimuli. Specific RET mutation variants have been found to correlate with phenotype and natural history of MTC with some defects portending a more aggressive clinical course. Greater understanding of the consequence of the aberrant signaling pathway has fostered the development of targeted therapies. Two small-molecule tyrosine kinase inhibitors, vandetanib and cabozantinib, are currently available as approved agents for the treatment of advanced or progressive MTC and provide significant increases in progression-free survival. Since there have been no head-to-head comparisons, clinicians often select between these agents on the basis of familiarity, patient characteristics, comorbidities, and toxicity profile.     

Leukemia inhibitory factor can mediate Ras/Raf/MEK/ERK-induced growth inhibitory signaling in medullary thyroid cancer cells

Medullary thyroid carcinoma (MTC) is a multiple endocrine neoplasia type 2 syndrome caused by mutations in extracellular receptor or intracellular kinase domains of the RET proto-oncogene. Activation of the Ras/Raf/MEK/ERK pathway can lead to growth arrest by secreting leukemia inhibitory factor (LIF) in MTC cells harboring a RET receptor domain mutation. Here, we report that Ras/Raf/MEK/ERK can also mediate, via LIF, growth inhibition in MTC cells harboring a RET kinase domain mutation. Ras/Raf/MEK/ERK activation was sufficient to induce growth inhibition and LIF expression in the human MTC line MZ-CRC-1. Presence of LIF-mediated signaling was determined by blocking the activity of culture medium conditioned by Raf-activated cells using anti-LIF neutralizing antibody. In addition, recombinant LIF effectively suppressed cell proliferation via cell cycle arrest in G0/G1 phase. Expression of dominant negative STAT3 abrogated LIF effects, indicating that LIF mediates its signaling through the JAK/STAT3 pathway. These results suggest that growth inhibition and activation of the autocrine/paracrine signaling through LIF/JAK/STAT may be a common response to Ras/Raf activation in different MTC types, and justify further evaluation of LIF as a potential anticancer agent for MTC.     

Ultrasound features of medullary thyroid carcinoma correlate with cancer aggressiveness: a retrospective multicenter study

Background

Poor prognosis of medullary thyroid cancer (MTC) with suspicious ultrasound (US) features has been reported. The aim of the study was to investigate the association between preoperative US presentation and aggressiveness features of MTC. Also, US features of MTC were compared with those previously reported.

Methods

Study group comprised 134 MTC from nine different centers. Based on US presentation the nodules were stratified in “at risk for malignancy” (m-MTC) or “probably benign” (b-MTC) lesions.

Results

Eighty nine (66.4%) m-MTC and 45 (33.6%) b-MTC were found. Metastatic lymph nodes (p = 0.0001) and extrathyroid invasiveness (p < 0.0001) were more frequent in m-MTC. There was statistically significant correlation (p = 0.0002) between advanced TNM stage and m-MTC with an Odds Ratio 5.5 (95% CI 2.1–14.4). Mean postsurgical calcitonin values were 224 ± 64 pg/ml in m-MTC and 51 ± 21 in b-MTC (p = 0.003).

Conclusions

This study showed that sonographically suspicious MTC is frequently associated with features of aggressiveness, suggesting that careful preoperative US of MTC patients may better plan their surgical approach.     

miR-19b-3p靶向MTUS1调控甲状腺髓样癌细胞凋亡的分子机制

背景与目的:miR-19b-3p在胃癌、前列腺癌等恶性肿瘤中均呈高表达,其可能作为肿瘤早期诊断及评估患者预后的潜在生物标志物.利用TargetScan靶基因预测软件筛选出的微管相关肿瘤抑制基因1(microtubule-associated tumor suppressor gene 1,MTUS1)可能为miR-19...     

Neck management in medullary thyroid carcinoma

Aims

The aims of this study were to retrospectively evaluate incidence and patterns of lymph node metastases, surgical treatment and prognostic factors of medullary thyroid carcinoma.

Methods

Out of a group of 70 MTC patients data of 67 patients were collected. Sixty-two of these patients underwent surgery. Apart from thyroidectomy, 16 patients underwent a bilateral neck dissection, 21 a unilateral neck dissection and 29 a paratracheal dissection or node-picking operation. Thirty-six patients were irradiated, of which 31 postoperatively and five with palliative intent.

Results

Lymph node metastases were found in 91% of the ipsilateral neck dissection specimens, 91% of the paratracheal dissections and 63% of the contralateral dissections. Of the 12 elective neck dissections, 5 were tumor positive. Level VI was positive in 91% of the cases where a dissection was done, whereas preoperatively only 16% were scored tumor positive. During follow-up 22 of the 67 patients developed one or more locoregional recurrences (in total 28 recurrences). The most important factors that were correlated with a worse prognosis of survival were late stage of disease (stage III and IV) (p = 0.0014), high number of positive lymph nodes (p = 0.0023) and incomplete surgical resection (p = 0.0002).

Conclusions

The high rate of locoregional recurrences in this study are a strong argument for a more aggressive approach to the primary and neck. A routine central and ipsilateral selective neck dissection of levels II–V should be considered in all MTC patients based on the high incidence of metastases and the relative low morbidity of a unilateral neck dissection. Patients referred after thyroidectomy alone with elevated (stimulated) calcitonin levels should be re-operated, performing an elective or therapeutic central and unilateral neck dissection.