中国科技论文统计源期刊 中文核心期刊
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊
日本科学技术振兴机构数据库（JST）
第七届湖北十大名刊提名奖
质子泵抑制药(PPI)是目前治疗酸相关性疾病的首选药物。近年来,越来越多研究发现长期应用PPI可能与胃黏膜病变相关,甚至导致胃癌的发生。该文通过检索国内外文献,对PPI的药理作用、致癌机制及相关临床研究进行阐述。旨在为临床合理选择和使用PPI,识别胃癌的高危人群,减少PPI相关性胃癌的发生提供参考。
Proton pump inhibitors(PPI)are the first choice for the treatment of acid-related diseases currently.However,in recent years,more and more studies have found that long-term use of PPI may be associated with gastric mucosal lesions,which even lead to the occurrence of gastric cancer.This article describes the pharmacological effects,carcinogenic mechanisms,and related clinical research results of PPI by investigating domestic and international literatures.This paper is to provide a reference for the rational selection and use of PPI,to identify high-risk groups of gastric cancer,and to reduce the incidences of PPI-related gastric cancer.
开放科学(资源服务)标识码(OSID)
胃癌是最常见的恶性实体瘤之一,是癌症相关死亡的第三大原因[1]。其重要危险因素包括男性老年、种族、幽门螺杆菌(
PPI为酸诱导活化的前体药物,其主要结构由一个吡啶环和一个苯并咪唑环及各种类型支链组成。由于PPI为弱碱化合物,其一级pKa在3.8~4.9,因此可以迅速穿透胃壁细胞膜,选择性地在胃壁细胞分泌小管中(pH值约为1)聚集。这种酸空间依赖性是PPI发挥治疗作用的第一个重要特性,可以使PPI在分泌小管中的浓度比在血液中的浓度高约1000倍 [6]。第二个重要步骤是PPI从累积的前体药物到活化物质的酸依赖性转化过程,即通过与分泌小管膜上质子泵上的氢离子(H+)相结合,结合后PPI失去膜穿透性,在高酸的环境下转化为亚磺酸或亚磺酰胺,亚磺酰胺再与质子泵中α-亚基中的一个或多个半胱氨酸分子的SH残基共价结合形成二硫键,从而不可逆抑制质子泵的酸分泌功能,阻断胃酸分泌的最后步骤。由于共价结合,其抑酸作用持续时间比血浆半衰期长得多。
有研究表明,胃壁细胞中25%的质子泵将在24 h内被新合成的泵取代[7],新质子泵产生后,胃壁细胞才能恢复泌酸功能,因此这也是PPI抑酸作用强、时间长的原因。即使在长期连续给药后,其酸抑制作用也不会降低,这与H2受体拮抗剂(H2RA)不同。由于所有目前可用的PPI具有相同的分子结构,因此PPI类药物都具有相似的药理学特征。此外,PPI不但可以抑制基础胃酸的分泌,对于乙酰胆碱、组胺及胃泌素等刺激产生的胃酸也有良好的抑制作用。
目前,长期应用PPI 与胃癌发生的关联,研究者比较认可的机制是PPI通过胃酸的分泌减少介导的高胃泌素血症[8]。胃泌素是一种多功能的多肽激素,主要由胃窦和上段小肠黏膜G细胞分泌产生,既可以直接作用于胃壁细胞刺激产生胃酸,也可以通过刺激肠嗜铬样(enterochromaffin-like,ECL)细胞分泌组胺间接促进胃酸分泌,还可以促进细胞生长[9]。PPI通过降低胃酸分泌、升高胃内pH值,对G细胞产生负反馈作用,从而增加血浆胃泌素浓度。由于ECL表面高度表达胆囊收缩素-2(cholecystokinin-2,CCK-2)受体,而该受体是胃泌素的靶细胞,因此高胃泌素会刺激ECL的增殖,造成胃底黏膜ECL数量的增加,并且可能造成胃神经内分泌肿瘤(neuroendcrine tumors,NETs)的形成[10]。生长抑素介导的胃泌素释放对胃窦G细胞的负反馈作用也经常被长期使用PPI和其他抗酸药引起的胃酸过少所抑制,从而导致高胃泌素血症和胃黏膜或ECL细胞增生[11]。李聪等[12]在研究短期和长期使用埃索美拉唑对大鼠胃黏膜的影响中发现,埃索美拉唑不但通过GAS对胃黏膜产生影响,并呈一定的时间和剂量依赖性,短期用药主要影响ECL细胞增殖,长期使用还会影响壁细胞增生,大剂量应用可能导致胃主细胞和D细胞减少。LUNDELL等[8]进行一项系统回顾性研究中,纳入1920例长期服用PPI 的患者,结果表明,长期(>3年)使用PPI者,其平均胃泌素水平上升到1~3倍正常上限,并怀疑胃泌素的升高在胃癌发展中起促进作用[13,14,15]。
目前胃类癌肿瘤分为3型[16],1型为伴有高泌素血症,生物学特性良好,很少侵入胃壁或转移到远处器官;2型为伴有多发性内分泌腺瘤,3型为不伴有高泌素血症,通常为恶性[17,18]。有研究发现高级别慢性萎缩性胃炎患者血浆中胃泌素浓度增加,偶尔会出现1型胃神经内分泌肿瘤[19,20],但这种类癌的风险很低,一项研究[21]表明接受不同剂量埃索美拉唑治疗1326例患者,随访6~12个月进行连续胃活检,5%~12%患者在最终活检中检测到单个、线性或小结节性增生。然而没有ECL细胞发育不良,类癌或瘤形成的情况。而基于对实验动物进行的研究,发现长期PPI给药至少在啮齿动物中发展伴随高胃泌素血症的胃神经内分泌肿瘤[22]。第二个可能机制为在高胃泌素条件下,如慢性萎缩性胃炎或长期使用PPI时,胃泌素本身对泌酸黏膜以及ECL细胞具有营养作用[23]。一项动物研究表明,对Hp感染的蒙古沙鼠进行高盐饮食可显著增加血清胃泌素水平和黏膜炎症,而这种现象可通过使用胃泌素拮抗剂得到改善[24]。
CHEUNG等[25]研究表明,在接受根除治疗的Hp感染患者中,PPI的使用与胃癌呈正相关。该研究纳入63 000例成人Hp感染患者,患者接受基于克拉霉素的三联疗法。为消除原发性偏倚,在研究前6个月或Hp根除治疗后12个月内被诊断胃癌患者排除。此外,尽量减少Hp诱导胃癌发生的影响,仅招募成功接受根除治疗的患者。结果提示PPI的使用显著增加患胃癌的风险。且PPI与胃癌之间的正相关性提示与剂量和持续时间呈依赖关系。这项研究具有重要意义,因为它证明长期使用PPI后胃癌的风险增加,即使在成功根除Hp后也是如此。
TRAN-DUY等[26]对三项观察性研究的系统评价显示,PPIs与胃癌风险增加有关[
CHEUNG等 [25]还进行一项全区域的回顾性队列研究,旨在分析Hp根除患者中使用PPI与胃癌的关系。结果表明,PPI的使用(定义为至少每周使用)与胃癌风险增加相关[
日本的一项研究将3年间接受内镜检查时发现胃黏膜黑斑64例患者纳入研究,将黑斑的内镜检查结果定义为胃黏膜中的黑色素沉着[27]。结果64例黑斑患者中正在服用PPIs 44例(68.8%)。所有黑斑仅在胃底腺区域被识别。41例(64.1%)有多个(>10个)黑斑。这些黑斑根据部位分为两种不同的类型:扁平黏膜和胃底腺息肉。病理学上,胃壁细胞突起,胃底腺囊肿和胃底腺囊肿中褐色色素沉着分别为26例(76.5%),23例(67.6%)和6例(17.6%)。而这种黑斑被认为可能是PPI诱导的新型胃癌的一种。
在7项研究的荟萃分析中,WAN等[28]发现PPI导致胃癌的风险在亚洲人中比白人更为显著[
在瑞典的全国性研究[29]中,PPI的风险在男性[
动物研究表明,长效PPIs可能会产生更高的胃肿瘤风险,因为在更高浓度-时间条件下全身暴露更多,从而导致胃泌素刺激更多[32,33]。然而,荟萃分析结果表明,不同的PPI可以基于效力互换使用,这种效力反映在24 h内pH值>4的百分比时间(奥美拉唑30 mg相当于兰索拉唑30 mg、埃索美拉唑20 mg和雷贝拉唑20 mg)[34]。
美国食品药品管理局(FDA)对61 864例PPI使用者进行长期随访研究发现,不同的年龄、性别、Hp治疗、累积PPI使用量和PPI使用总年数,泮托拉唑(长效PPI)和其他短效PPI的胃癌风险相当[奥美拉唑,埃索美拉唑,兰索拉唑或雷贝拉唑的任意组合;
虽然一些研究表明长期使用PPI与胃癌风险之间存在显著关系。然而,由于研究设计的局限性和遗漏的主要混杂变量,目前结论还不能确定。此外,还存在冲突的数据,例如,尽管美国是最常见和长期使用的国家之一,但胃癌的发病率相对较低[35]。因此,需要更有力的证据,包括精心设计的大规模前瞻性研究,以支持长期PPI使用与胃癌之间的潜在关联。
PPI在胃癌中具有双重效应,除了长期应用可能导致胃癌发生外,在一定程度上也会对胃癌细胞产生抑制作用,进而影响胃癌发展。首先,肿瘤微环境通常发生酸度变化,如实体瘤中,细胞外pH值为酸性,细胞内pH值为中性至碱性,而正常组织中微环境pH值通常保持碱性。这种现象导致碱性较低的细胞毒性药物在细胞内浓度降低,例如顺铂、氟尿嘧啶、长春新碱或多柔比星[36]。而PPI通过抑制肿瘤细胞的液泡型ATP酶(V-ATPase),碱化肿瘤微环境并在细胞内靶标中保留弱碱性细胞毒性药物,从而有助于克服肿瘤细胞的耐药性并增强对细胞毒性药物的化学敏感性[37]。
其次,PPI对癌细胞干性的调节起一定作用。由于癌症干细胞(cancer stem cell,CSC)在化学抗药性的发展以及癌症转移中起着关键作用[38],而ATP结合盒(adenosine triphosphate-binding cassette,ABC)转运蛋白的几种家族蛋白,例如P-糖蛋白、多药耐药相关蛋白1(multidrug resistance-associated protein-1,MRP-1)、肺部耐药相关蛋白(lung resitance-related protein,LRP)和乳腺癌耐药蛋白(breast cancer resistance protein,BCRP)在CSC中高度表达,并通过增强药物外排泵的活性来促进MDR[39]。PPI可通过修饰厌氧糖酵解和ABC转运蛋白来降低固体癌细胞的化学耐药性[40]。
PPI调制蛋白酪氨酸磷酸酶1(scr-homology domain 2-containing protein tyrosine phosphatase-1,SHP-1)/信号转导和转录激活因子3(singnal transducer and activator of transcription 3,STAT3)信号轴是其抑制胃癌进展的另一重要原因。由于磷酸化的STAT3通过上调胃癌细胞中相关的靶基因(如波形蛋白和存活蛋白)从而诱导上皮-间质转化(epithelial-mesenchymal transition,EMT)[41,42,43],还可以激活周围的免疫细胞,以调节有利于癌细胞存活的各种免疫反应。因此,STAT3可能是抑制胃癌侵袭的主要靶标。SHP-1可作为STAT3活性的有效抑制剂,诱导STAT3去磷酸化。最新研究证明PPI可以剂量依赖的方式有效地诱导SHP-1并下调胃癌细胞中磷酸化的STAT3水平,从而在抑制胃癌的进展中起作用[44]。
某些临床情况可能需要长期使用PPI,如阿司匹林/ 非甾体抗炎药(nonsterodial antiinflammatory drugs,NSAID)相关上消化道出血,对于高风险的个体应长期给予PPI[45]。巴雷特(Barrett)食管是另一种建议长期使用PPI的疾病[46]。如果需要长期使用PPI,建议对Hp进行检测并根除,以防止胃萎缩的发展,从而降低胃癌的风险[47]。还有人建议将非空腹嗜铬粒蛋白A用作长期PPI使用者的血清学标志物,以监测ECL细胞增生的程度[48]。此外,由于约1/4的PPI使用者胃泌素水平为200~400 pg·mL-1,因此认为通过监测胃泌素水平有可能识别出胃癌的高风险患者。且这种监测还可以为前瞻性研究提供良好的生物标志物,以及鉴定可能受益于PPI剂量减小或使用替代方法的患者[49]。
尽管PPI具有潜在的有害作用,但迄今为止仍是治疗PUD、GERD和预防阿司匹林/ NSAID相关上消化道出血的最有效疗法。因此应该促进合理使用PPI,以尽量减少与长期使用相关的任何潜在副作用,而不是非理性避免使用。总之,医生应该在有限的治疗期内考虑PPI的最小有效剂量,特别是对于非侵袭性GERD和非溃疡性消化不良。
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Gastric cancer is the third cause of cancer death worldwide, and Helicobacter pylori infection causes almost 90% of non-cardia cancers, the predominant type. H. pylori infection is treatable, and in clinical trials there is evidence of a 30-40% reduction in incidence of gastric cancer among treated subjects. However, with a few exceptions, there are no public health programmes for gastric cancer prevention. In December 2013, the International Agency for Research on Cancer (IARC), organized a Working Group of international experts to discuss and make recommendations for gastric cancer control. The Working Group considered that the enormous burden of disease, which is not expected to decline in the coming decades, requires decisive public health action to include gastric cancer in cancer control programmes. Interventions should be tailored to the local conditions and consider population-based screening and eradication of H. pylori, in the context of evaluation of feasibility, efficacy and adverse consequences.
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Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.
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BACKGROUND & AIMS: The purpose of this review is to evaluate the risks associated with long-term use of proton pump inhibitors (PPIs), focusing on long-term use of PPIs for three common indications: gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and non-steroidal anti-inflammatory drug (NSAID) bleeding prophylaxis. METHODS: The recommendations outlined in this review are based on expert opinion and on relevant publications from PubMed, EMbase, and the Cochrane library (through July 2016). To identify relevant ongoing trials, we queried clinicaltrials.gov. To assess the quality of evidence, we used a modified approach based on the GRADE Working Group. The Clinical Practice Updates Committee of the American Gastroenterological Association has reviewed these recommendations. Best Practice Advice 1: Patients with GERD and acid-related complications (ie, erosive esophagitis or peptic stricture) should take a PPI for short-term healing, maintenance of healing, and long-term symptom control. Best Practice Advice 2: Patients with uncomplicated GERD who respond to short-term PPIs should subsequently attempt to stop or reduce them. Patients who cannot reduce PPIs should consider ambulatory esophageal pH/impedance monitoring before committing to lifelong PPIs to help distinguish GERD from a functional syndrome. The best candidates for this strategy may be patients with predominantly atypical symptoms or those who lack an obvious predisposition to GERD (eg, central obesity, large hiatal hernia). Best Practice Advice 3: Patients with Barrett's esophagus and symptomatic GERD should take a long-term PPI. Best Practice Advice 4: Asymptomatic patients with Barrett's esophagus should consider a long-term PPI. Best Practice Advice 5: Patients at high risk for ulcer-related bleeding from NSAIDs should take a PPI if they continue to take NSAIDs. Best Practice Advice 6: The dose of long-term PPIs should be periodically reevaluated so that the lowest effective PPI dose can be prescribed to manage the condition. Best Practice Advice 7: Long-term PPI users should not routinely use probiotics to prevent infection. Best Practice Advice 8: Long-term PPI users should not routinely raise their intake of calcium, vitamin B12, or magnesium beyond the Recommended Dietary Allowance (RDA). Best Practice Advice 9: Long-term PPI users should not routinely screen or monitor bone mineral density, serum creatinine, magnesium, or vitamin B12. Best Practice Advice 10: Specific PPI formulations should not be selected based on potential risks.
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DOI:10.5056/jnm18001
URL
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BACKGROUND: Proton pump inhibitors (PPIs) have a well-established safety profile. However, concerns have been raised about a potential relationship between PPI-induced hypergastrinaemia and the development of enterochromaffin-like (ECL) cell hyperplasia, neuroendocrine tumours and gastric cancer during long-term therapy. AIM: To review the effects of long-term PPI use on serum gastrin levels and gastric histopathology. METHODS: A systematic literature search was conducted in PubMed on 21 April 2015 to identify studies reporting the effects of long-term (defined as >3 years) PPI use on gastrin levels and gastric histopathology. RESULTS: A total of 16 studies (1920 patients) met the inclusion criteria. During long-term PPI therapy, mean gastrin levels rose to one to three times the upper limit of the normal range (~100 pg/mL), and an increased prevalence of ECL cell hyperplasia was observed (+7.8-52.0%). Helicobacter pylori-positive patients had a significantly increased risk of developing ECL linear/micronodular hyperplasia compared with H. pylori-negative patients [OR: 2.45 (95% CI: 1.47-4.10), P = 0.0006]; however, no evidence of neoplastic changes was found. The risk of corpus atrophy was markedly higher in H. pylori-positive patients than in H. pylori-negative patients [OR: 11.45 (95% CI: 6.25-20.99), P < 0.00001]. Not a single case of gastric adenocarcinoma was found. CONCLUSIONS: Long-term PPI therapy induced moderate hypergastrinaemia in most patients and an increased prevalence of ECL cell hyperplasia. H. pylori-positive patients receiving long-term PPI therapy were exposed to a higher risk of corpus atrophy than H. pylori-negative patients. No neuroendocrine tumours or gastric cancers were found.
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A 56-year-old man with gastroesophageal reflux disease (GERD) was referred to our hospital. Esophagogastroduodenoscopy (EGD) revealed no evidence of any polypoid lesions in the stomach, and the patient had no history of Helicobacter pylori infection. He received omeprazole (20 mg) once daily for the GERD. EGD was performed at 1 year after the start of omeprazole administration, and this time, gastric hyperplastic polyps (GHPs) were detected. The GHPs increased in size as the omeprazole treatment continued, but they markedly decreased in size following omeprazole discontinuation. Thus, the administration of proton pump inhibitors may be a risk factor for the development of GHP independent of H. pylori infection.
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Recently, two epidemiological studies showed that long-term treatment with proton pump inhibitors (PPIs) increased the risk of gastric cancer. It is well known that hypergastrinemia predisposes to gastric neoplasia in animals as well as man. Recently a study showed that hypergastrinemic patients had an increased risk of gastric cancer when followed for about 25 years. It is likely that hypergastrinemia is the pathogenic factor for gastric carcinogenesis due to PPI. PPI are the only group of drugs that causes long-term hypergastrinemia in the doses used in a clinical setting. Due to the likely carcinogenic effect, PPIs should be used carefully. Moreover, since the carcinogenic effect of Helicobacter pylori (Hp) infection also may be mediated by an increase in gastrin, Hp should be eradicated whenever treatment with PPI is initiated. In peptic ulcer disease Hp eradication is the treatment of choice. Gastro-oesophageal reflux disease (GERD) is the most prevalent condition leading to long-term use of inhibitors of gastric acid secretion. Only in severe oesophagitis should the treatment be initiated by PPIs, whereas histamine-2 (H-2) blockers ought to be the initial option in most cases of GERD particularly since PPI treatment induces tolerance to H-2 blockers. In the cases where long-term PPI treatment is necessary, the dose should be adjusted by the determination of chromogranin A, which in a way reflects 24-h gastrin exposure. Finally, due to latency of neoplasia, the use of PPI must be very restricted in children and young adults.
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The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca(2+), whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca(2+) homeostatic capacity. Luminal nutrients, such as Ca(2+) and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca(2+), amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca(2+), peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca(2+) homeostasis should be reviewed for effects outside traditional Ca(2+)-regulating tissues in view of the broader distribution and function of CaR.
[本文引用:1]
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| [12] |
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| [13] |
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| [14] |
Gastric enterochromaffin-like cell carcinoids have been detected in rats exposed lifelong to omeprazole. By inhibiting acid secretion, omeprazole causes hypergastrinemia which, with prolonged exposure, exerts a trophic effect on enterochromaffin-like cells with eventual enterochromaffin-like cell carcinoid formation in some animals. This mechanism seems to explain the appearance of enterochromaffin-like cell carcinoids in human hypergastrinemic states, whether associated with hyperchlorhydria, eg, Zollinger-Ellison syndrome, or with hypochlorhydria, eg, pernicious anemia (nonantral atrophic gastritis). Omeprazole produces modest serum gastrin elevations in humans when monitored over a 24-hr period. Gastrin levels are markedly lower and less sustained than in the above hypergastrinemic states. Extensive gastric biopsy data from patients enrolled in long-term studies indicate that omeprazole administration is not associated with clinically significant changes in the human oxyntic endocrine cell population. Man and rat differ markedly both in their gastrin response to a given level of acid inhibition and in their response to the trophic influence of gastrin on enterochromaffin-like cells. The rat model is a false indicator of risk in man.
[本文引用:1]
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| [15] |
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| [16] |
DOI:10.1159/000080734
URL
[本文引用:1]
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| [17] |
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| [18] |
BACKGROUND AND AIM: Type I gastric carcinoids (TIGC) are associated with chronic atrophic gastritis (CAG) with hypergastrinemia and hyperplasia of enterochromaffin-like cells. Several treatment options are currently available for these tumors including total gastrectomy, partial resection, antrectomy, endoscopic resection and endoscopic surveillance. The present study evaluated different treatment approaches and clinical outcomes of patients with TIGC in Japan. METHODS: Between 1991 and 2011, 82 patients with TIGC were identified at multicenter institutions in Japan. Patient demographics, tumor size, depth of invasion, vessel involvement, treatment approach, Helicobacter pylori infection, serum gastrin level, recurrence-free survival (RFS) and disease-specific survival (DSS) were analyzed. RESULTS: Median age of all patients at the time of diagnosis was 56 years (range, 24-79 years). There were 44 males and 38 females. Patients underwent endoscopic surveillance (n=25), endoscopic resection (n=41) or surgical resection (n=16). Intramucosal invasion was found in 19 patients, submucosal invasion in 44 patients and muscularis propria invasion in one patient. Tumor diameter was /= 21 mm in five patients. None of the patients showed rapidly growing tumors, local recurrence or metastasis. The median (range) follow-up period was 7(0-20) years. RFS was 97.6% and DSS was 100% in all the patients. CONCLUSION: The prognosis of TIGC patients treated by different modalities in Japan is favorable regardless of the generational change of management for TIGC.
[本文引用:1]
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| [19] |
The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis.
[本文引用:1]
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| [20] |
Proton pump inhibitors are potent drugs for the treatment of acid-related diseases. The moderate hypergastrinaemia observed during therapy is a physiological response to low intragastric pH and the increase is limited to the first months of therapy with no further changes thereafter. Reports on endocrine cell changes in the antral mucosa under chronic PPI therapy are controversial and lack clinical relevance. In contrast, in the oxyntic mucosa hyperplastic argyrophil cell changes have been reported, dependent on the degree and duration of hypergastrinaemia, the severity of oxyntic mucosal gastritis, especially atrophy, and the presence of H. pylori infection. Current data do not support a progression from hyperplastic to dysplastic argyrophil cell lesions in humans in the absence of additional genetic factors. Data on the progression of oxyntic gastritis under chronic PPI treatment in comparison to untreated controls could not be confirmed in more recent studies including a well-matched control population. The main factor for gastritis progression is the presence of Helicobacter pylori infection. The bacterium not only causes a chronic inflammation of the gastric mucosa, resulting in atrophy and intestinal metaplasia, but also influences endocrine cell populations involved in the regulation of gastric acid secretion. The clinical benefit of H. pylori eradication in reflux esophagitis patients is still a matter of debate. The complex relations in humans between hypergastrinaemia, (oxyntic) gastritis and atrophy, H. pylori infection, argyrophil cell hyperplasia, and the effects of long-term PPI treatment of acid-related diseases do not allow a quantification of the contribution of each single factor for the observed changes.
[本文引用:1]
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| [21] |
OBJECTIVE: The aim of this study was to determine the effect of 6-12 months of treatment with esomeprazole on the histopathology of the gastric mucosa. METHODS: Two identically designed, randomized, placebo-controlled trials of esomeprazole 40, 20, or 10 mg daily for up to 6 months, as well as a noncomparative, multicenter trial of esomeprazole 40 mg daily for up to 12 months, were conducted in 1326 patients with healed erosive esophagitis (1294 negative for Helicobacter pylori [H. pylori]). Gastric biopsy samples were obtained before treatment and on completion of (or discontinuation from) the trials. Samples were evaluated for the presence of H. pylori, characteristics of acute gastritis or atrophic gastritis, and enterochromaffin-like cell pathology. RESULTS: During treatment with esomeprazole, the number of patients with an improvement in gastric histological scores was typically greater than or equal to the number who worsened. Gastric histological scores worsened for each corporal or antral characteristic of gastritis in <6.2% of patients. Histological scores with esomeprazole and placebo were similar throughout the 6-month trials. Only one among 1326 patients treated with esomeprazole (H. pylori negative) had evidence of treatment-emergent atrophic gastritis. On final biopsy, 5-12% of patients had abnormal enterochromaffin-like cell scores (simple, linear, or micronodular hyperplasia). There were no instances of enterochromaffin-like cell dysplasia, carcinoids, or neoplasia. CONCLUSIONS: Patients with healed erosive esophagitis receiving esomeprazole for up to 12 months had minor fluctuations in gastric histological scores, similar to those experienced in untreated populations. Use of esomeprazole did not raise any safety concerns with respect to the development of atrophic gastritis, or cause clinically significant changes in enterochromaffin-like cells.
[本文引用:1]
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| [22] |
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| [23] |
The gastric hormone gastrin plays a role in organizing the gastric mucosa. Gastrin also regulates the expression of genes that have important actions in extracellular matrix modelling, including plasminogen activator inhibitor (PAI)-1 which is part of the urokinase plasminogen activator (uPA) system. The uPA system (including PAI-1) is associated with cancer progression, fibrosis and thrombosis. Its biological role in the stomach and molecular mechanisms of action are not well understood. The aim of this study was to examine the effect of PAI-1 on the trophic changes observed in gastric corpus mucosa in hypergastrinemia using PAI-1 and/or HK-ATPase beta subunit knockout (KO) mice. HK-ATPase beta subunit KO mice were used as a model of hypergastrinemia. In 12 month old female mice, intragastric acidity and plasma gastrin were measured. The stomachs were examined for macroscopic and histological changes. In mice null for both PAI-1 and HK-ATPase beta (double KO), there was exaggerated hypergastrinemia, increased stomach weight and corpus mucosal thickness, and more pronounced trophic and architectural changes in the corpus compared with HK-ATPase beta KO mice. Genome-wide microarray expression data for the gastric corpus mucosa showed a distinct gene expression profile for the HK-ATPase beta KO mice; moreover, enrichment analysis revealed changes in expression of genes regulating intracellular processes including cytoskeleton remodelling, cell adhesion, signal transduction and epithelial-to-mesenchymal transition (EMT). Genes differentially expressed in the double KO compared with HK-ATPase beta KO mice included the transcription factor Barx2 and the chromatin remodeler gene Tet2, which may be involved in both normal gastric physiology and development of gastric cancer. Based on the present data, we suggest that PAI-1 plays a role in maintaining gastric mucosal organization in hypergastrinemia.
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| [24] |
Intake of salt and salty food is known as a risk factor for gastric carcinogenesis. To examine the dose-dependence and the mechanisms underlying enhancing effects, Mongolian gerbils were treated with N-methyl-N-nitrosourea (MNU), Helicobacter pylori and food containing various concentrations of salt, and were sacrificed after 50 weeks. Among gerbils treated with MNU and H. pylori, the incidences of glandular stomach cancers were 15% in the normal diet group and 33%, 36% and 63% in the 2.5%, 5% and 10% NaCl diet groups, showing dose-dependent increase (p < 0.01). Intermittent intragastric injection of saturated NaCl solution, in contrast, did not promote gastric carcinogenesis. In gerbils infected with H. pylori, a high salt diet was associated with elevation of anti-H. pylori antibody titers, serum gastrin levels and inflammatory cell infiltration in a dose-dependent fashion. Ten percent NaCl diet upregulated the amount of surface mucous cell mucin (p < 0.05), suitable for H. pylori colonization, despite no increment of MUC5AC mRNA, while H. pylori infection itself had an opposing effect, stimulating transcription of MUC6 and increasing the amount of gland mucous cell mucin (GMCM). High salt diet, in turn, decreased the amount of GMCM, which acts against H. pylori infection. In conclusion, the present study demonstrated dose-dependent enhancing effects of salt in gastric chemical carcinogenesis in H. pylori-infected Mongolian gerbils associated with alteration of the mucous microenvironment. Reduction of salt intake could thus be one of the most important chemopreventive methods for human gastric carcinogenesis.
[本文引用:1]
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| [25] |
OBJECTIVE: Proton pump inhibitors (PPIs) is associated with worsening of gastric atrophy, particularly in Helicobacter pylori (HP)-infected subjects. We determined the association between PPIs use and gastric cancer (GC) among HP-infected subjects who had received HP therapy. DESIGNS: This study was based on a territory-wide health database of Hong Kong. We identified adults who had received an outpatient prescription of clarithromycin-based triple therapy between year 2003 and 2012. Patients who failed this regimen, and those diagnosed to have GC within 12 months after HP therapy, or gastric ulcer after therapy were excluded. Prescriptions of PPIs or histamine-2 receptor antagonists (H2RA) started within 6 months before GC were excluded to avoid protopathic bias. We evaluated GC risk with PPIs by Cox proportional hazards model with propensity score adjustment. H2RA was used as a negative control exposure. RESULT: Among the 63 397 eligible subjects, 153 (0.24%) developed GC during a median follow-up of 7.6 years. PPIs use was associated with an increased GC risk (HR 2.44, 95% CI 1.42 to 4.20), while H2RA was not (HR 0.72, 95% CI 0.48 to 1.07). The risk increased with duration of PPIs use (HR 5.04, 95% CI 1.23 to 20.61; 6.65, 95% CI 1.62 to 27.26 and 8.34, 95% CI 2.02 to 34.41 for >/=1 year, >/=2 years and >/=3 years, respectively). The adjusted absolute risk difference for PPIs versus non-PPIs use was 4.29 excess GC (95% CI 1.25 to 9.54) per 10 000 person-years. CONCLUSION: Long-term use of PPIs was still associated with an increased GC risk in subjects even after HP eradication therapy.
[本文引用:2]
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| [26] |
BACKGROUND & AIMS: There have been increasing numbers of case reports and observational studies of adverse events in patients receiving long-term therapy with proton pump inhibitors (PPIs). The effects of PPI therapy on risks of fundic gland polyps (FGPs) and gastric cancer have received considerable attention. We performed a systematic review with a meta-analysis of randomized controlled trials and observational studies that assessed these risks. METHODS: We searched the PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials databases for relevant studies published through July 2015. We calculated pooled odds ratio for FGPs and the risk ratio for gastric cancer in PPI users compared with PPI nonusers using fixed- and random-effects models. RESULTS: We analyzed data from 12 studies, comprising more than 87,324 patients: 1 randomized controlled trial reporting the effect of PPIs on gastric polyps (location not specified), 6 cohort and 1 case-control studies on FGPs, and 1 cohort and 3 case-control studies on gastric cancer. Pooled odds ratios for FGPs were 1.43 (95% confidence interval, 1.24-1.64) and 2.45 (95% confidence interval, 1.24-4.83) from fixed- and random-effects models, respectively. The pooled risk ratio for gastric cancer was 1.43 (95% confidence interval, 1.23-1.66) from each model. We observed significant heterogeneity among studies reporting on FGPs, but not among studies reporting on gastric cancer. CONCLUSIONS: Based on a systematic review with meta-analysis, long-term use of PPIs (>/=12 months) is associated with an increased risk of FGPs. PPI therapy might also increase the risk of gastric cancer, but this association could be biased, because of the limited number of studies and possible confounding factors.
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| [27] |
Objective We have recently discovered new gastric lesions with black spots. There have been no reports about black spots and their clinicopathological features. We therefore report the clinicopathological features of black spots and assess their causes and mechanisms. Methods Sixty-four patients with black spots among 26,620 Japanese patients that underwent endoscopy between May 2012 and October 2014 were enrolled. Endoscopic findings of black spots were defined as black pigmentations in the gastric mucosa by conventional endoscopy. We investigated the clinicopathological characteristics, including gender, age, underlying diseases and medications, endoscopic and pathologic findings of patients with black spots. Results The prevalence of patients with black spots was 0.24%. Of sixty-four cases, 44 (68.8%) were taking proton pump inhibitors (PPIs). Eight (12.5%) were taking corticosteroids. There were 10 cases (15.6%) with decreased renal function. All black spots were identified only in the fundic gland region. Forty-one (64.1%) patients had multiple (more than ten) black spots. There were two different types: black spots on the flat mucosa and black spots on fundic gland polyps. Pathologically, parietal cell protrusions, fundic gland cysts and brownish pigmentation in fundic gland cysts were seen in 26 (76.5%), 23 (67.6%) and 6 (17.6%) patients, respectively. Conclusion We herein describe gastric black spots as a new gastric mucosal finding that arises only in the fundic gland region. The black spots are pathologically brownish pigmentations in fundic gland cysts. Adverse events of PPIs and parietal cell protrusion caused by PPI use are strongly considered to be one of the etiologies of black spots.
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| [28] |
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OBJECTIVE: Proton pump inhibitors (PPIs) are among the most commonly prescribed drugs. Concerns have been raised about a potentially increased risk of gastric cancer following long-term use. Our aim is to assess the risk of gastric cancer associated with PPI use, taking into account underlying indications. DESIGN: This is a population-based cohort study. Standardised incidence ratios (SIRs) and 95% CIs were calculated to compare the risk of gastric cancer among long-term PPI users with the corresponding background population, while taking confounding by indication into account. SETTING: Population-based study in Sweden (2005-2012). PARTICIPANTS: This study included virtually all adults residing in Sweden exposed to maintenance therapy with PPIs. EXPOSURE/INTERVENTION: Maintenance use of PPIs, defined as at least 180 days during the study period. Maintenance use of histamine 2 receptor antagonist was evaluated for comparison reasons. OUTCOME MEASURES: Gastric cancer (cardia and non-cardia), and subgroup analysis for gastric adenocarcinoma, as defined by the Swedish Cancer Registry. RESULTS: Among 797 067 individuals on maintenance PPI therapy, the SIR of gastric cancer was over threefold increased (SIR=3.38, 95% CI 3.23 to 3.53). Increased SIRs were found in both sexes and all age groups, but were especially increased among PPI users younger than 40 years (SIR=22.76, 95% CI 15.94 to 31.52). Increased SIRs were found for each indication studied, including those without an association with gastric cancer, for example, gastro-oesophageal reflux (SIR=3.04, 95% CI 2.80 to 3.31), and those with a supposedly decreased risk, for example, aspirin users (SIR=1.93, 95% CI 1.70 to 2.18). The association was similar for cardia and non-cardia gastric cancer. Analyses restricted to adenocarcinoma showed similar results to those for all gastric cancers. Long-term users of histamine 2 receptor antagonists, which have the same indications as PPIs, were not at any increased risk. CONCLUSIONS: Long-term PPI use might be an independent risk factor for gastric cancer. This challenges broad maintenance PPI therapy, particularly if the indication is weak.
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| [30] |
BACKGROUND & AIMS: Atrophic corpus gastritis (ACG) is believed to be an early precursor of gastric adenocarcinoma. We aimed to investigate trends of ACG in Northern Sweden, from 1990 through 2009, and to identify possible risk factors. METHODS: We randomly selected serum samples collected from 5284 participants in 1990, 1994, 1999, 2004, and 2009, as part of the population-based, cross-sectional Northern Sweden Multinational Monitoring of Trends and Determinants in Cardiovascular Disease study (ages, 35-64 y). Information was collected on sociodemographic, anthropometric, lifestyle, and medical factors using questionnaires. Serum samples were analyzed for levels of pepsinogen I to identify participants with functional ACG; data from participants with ACG were compared with those from frequency-matched individuals without ACG (controls). Blood samples were analyzed for antibodies against Helicobacter pylori and Cag pathogenicity island protein A. Associations were estimated with unconditional logistic regression models. RESULTS: Overall, 305 subjects tested positive for functional ACG, based on their level of pepsinogen I. The prevalence of ACG in participants age 55 to 64 years old decreased from 124 per 1000 to 49 per 1000 individuals between 1990 and 2009. However, the prevalence of ACG increased from 22 per 1000 to 64 per 1000 individuals among participants age 35 to 44 years old during this time period. Cag pathogenicity island protein A seropositivity was associated with risk for ACG (odds ratio, 2.29; 95% confidence interval, 1.69-3.12). Other risk factors included diabetes, low level of education, and high body mass index. The association between body mass index and ACG was confined to individuals age 35 to 44 years old; in this group, overweight and obesity were associated with a 2.8-fold and a 4.7-fold increased risk of ACG, respectively. CONCLUSIONS: Among residents of Northern Sweden, the prevalence of ACG increased from 1990 through 2009, specifically among adults age 35 to 44 years old. The stabilizing seroprevalence of H pylori and the increasing prevalence of overweight and obesity might contribute to this unexpected trend. Studies are needed to determine whether these changes have affected the incidence of gastric cancer.
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| [31] |
The worldwide incidence of gastric cancer is gradually declining, however it remains the fourth highest in cancer incidence and the second leading cause of cancer death. Gastric cancer in young people is a disturbing problem and the routine screening does not include people less than 35 years. The clinicopathological features of gastric carcinoma are said to differ between young and elderly patients and it is thought that the prognosis of this disease is worse for younger patients. It is also suggested that the diagnosis is usually made later or have a more aggressive behaviour. Although, others report that tumor staging and prognosis for young patients is similar to older patients and depends on whether the patients undergo a curative resection. All these data need more investigation and studies. Although Portugal has a high incidence of gastric cancer, no studies have yet been performed comparing the clinicopathologic features and prognosis of young and elderly patients with gastric cancer.
[本文引用:1]
This study intend to assess whether the clinicopathological features and prognosis of gastric cancer in young patients (YGC) is similar to older ones (OGC). Between 2000 and 2005, 406 patients with histological diagnosis of primary gastric cancer, treated in the Departments of Surgery and Oncology at the Centro Hospitalar of Vila Nova de Gaia / Espinho, were regularly followed at least for five years after surgery. These were reviewed retrospectively. Several variables were analyzed in young patients and compared with the elder ones. We used the chi-square and Fisher to evaluate the statistical association between categorical variables and t-test for numeric variables. Survival was estimated by the Kaplan-Meier method and used the log-rank test to assess differences in survival among different subgroups of patients. The criteria for statistical significance was p < 0.05. Data analysis was performed using the SPSS 18. With regard to resectability, 78 % of the tumors were resected in the group of younger patients, the surgery more frequently achieved was total gastrectomy with anastomosis in Y of Roux. In the elder group, about 62 % of the tumors were resected and BII gastrectomy was the most frequent surgery. The diffuse adenocarcinoma was the most frequent histological type in younger patients, whereas in older patients was intestinal adenocarcinoma. With regard to the stage in the first group there was a predominance of stages: IA and IV (26.1 %) in the second: IV (25.8 %). The survival for stage III e IV was significantly worst in YGC compared with OGC. |
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| [33] |
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| [34] |
Although proton pump inhibitors (PPIs) are widely used, their relative potency and ideal dosing regimens remain unclear. We analyzed data from randomized clinical trials that performed pH testing in patients receiving solid-dose PPI formulations (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) for a minimum of 5 days. We used omeprazole equivalency and the surrogate biomarker, percentage time pH > 4 over a 24-hour period (pH4time), to compare PPI effectiveness for different PPIs given once, twice, or 3 times daily. We found that increasing strength of once-daily PPIs (9-64 mg omeprazole equivalents) increased pH4time linearly from approximately 10.0 to 15.6 hours; higher doses produced no further increase in pH4time. Increasing the frequency to twice-daily PPI increased pH4time linearly, from approximately 15.8 to 21.0 hours. Three-times daily PPIs performed similarly to twice-daily PPIs. The costs of PPIs varied greatly, but the cost variation was not directly related to potency. We conclude that PPIs can be used interchangeably based on potency. Using twice-daily PPIs is more effective in increasing efficacy increasing once-daily PPI dosage. Omeprazole and lansoprazole (30 mg) and 20 mg of esomeprazole rabeprazole are functionally equivalent.
[本文引用:2]
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| [35] |
Proton pump inhibitors (PPIs) were clinically introduced more than 25 years ago and have since proven to be invaluable, safe, and effective agents for the management of a variety of acid-related disorders. Although all members in this class act in a similar fashion, inhibiting active parietal cell acid secretion, there are slight differences among PPIs relating to their pharmacokinetic properties, metabolism, and Food and Drug Administration (FDA)-approved clinical indications. Nevertheless, each is effective in managing gastroesophageal reflux disease and uncomplicated or complicated peptic ulcer disease. Despite their overall efficacy, PPIs do have some limitations related to their short plasma half-lives and requirement for meal-associated dosing, which can lead to breakthrough symptoms in some individuals, especially at night. Longer-acting PPIs and technology to prolong conventional PPI activity have been developed to specifically address these limitations and may improve clinical outcomes.
[本文引用:1]
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| [36] |
Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis. A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H(+)-ATPases (V-H(+)-ATPases). V-H(+)-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H(+)-ATPase activity. A class of V-H(+)-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H(+)-ATPases. PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine. PPI pretreatment was associated with the inhibition of V-H(+)-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.
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| [37] |
Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg(-1)) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.
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| [38] |
Squamous cell carcinoma in the head and neck (HNSCC) is a common yet poorly understood cancer, with adverse clinical outcomes due to treatment resistance, recurrence, and metastasis. Putative cancer stem cells (CSCs) have been identified in HNSCC, and BMI1 expression has been linked to these phenotypes, but optimal treatment strategies to overcome chemotherapeutic resistance and eliminate metastases have not yet been identified. Here we show through lineage tracing and genetic ablation that BMI1(+) CSCs mediate invasive growth and cervical lymph node metastasis in a mouse model of HNSCC. This model and primary human HNSCC samples contain highly tumorigenic, invasive, and cisplatin-resistant BMI1(+) CSCs, which exhibit increased AP-1 activity that drives invasive growth and metastasis of HNSCC. Inhibiting AP-1 or BMI1 sensitized tumors to cisplatin-based chemotherapy, and it eliminated lymph node metastases by targeting CSCs and the tumor bulk, suggesting potential regimens to overcome resistance to treatments and eradicate HNSCC metastasis.
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| [39] |
Gastrin is the main hormone stimulating gastric acid secretion, but it exerts proliferative and anti-apoptotic actions on various cancer cell types, in addition to its well-known trophic effect on enterochromaffin-like cells. As treatment with proton pump inhibitors (PPIs) increases the biosynthesis and secretion of gastrin, it has been postulated that treatment with PPIs could increase the risk of cancer, especially in Barrett's esophagus, gastric carcinoids, and colorectal cancer (CRC). Some tumors produce gastrin of their own, which can act in an autocrine manner to promote tumor growth. In addition, gastrin is known to foster the tumor microenvironment. However, in spite of these potentially increased cancer risks due to PPI-induced hypergastrinemia, prospective, large-scale cohort studies did not show an increase in CRC prevalence. The question as to why the long-term use of PPIs was not associated with an increased cancer risk of CRC might be answered by the fact that the PPIs antagonized the trophic effects of hypergastrinemia. Furthermore, the blockade of proton pumps or potassium channels in cancer cells could limit the abnormal glycolytic energy metabolism of cancer cells. Apart from their suppressive effect on gastric acids, PPIs exert an anti-tumor effect through the selective induction of apoptosis as well as an anti-inflammatory effect, and they protect cells from developing chemo- or radiotherapeutic resistance. Moreover, the anti-carcinogenic actions of PPIs were augmented with PPI-induced hypergastrinemia. Together with their potential targeted killing of cancer stem cells, these effects demonstrate their potential anti-cancer actions.
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| [40] |
INTRODUCTION: Abundance of the ATPase-binding cassette (ABC) transporters and deranged self-renewal pathways characterize the presence of cancer stem cells (CSCs) in gastrointestinal cancers (GI cancers), which play crucial roles in tumorigenesis, chemotherapy resistance, tumor recurrence, and cancer metastasis. Therefore, in order to ensure high cure rates, chemoquiescence, CSCs should be ablated. Recent advances in either understanding CSCs or biomarker identification enable scientists to develop techniques for ablating CSCs and clinicians to provide cancer cure, especially in GI cancers characterized by inflammation-driven carcinogenesis. Areas covered: A novel approach to ablate CSCs in GI cancers, including esophageal, gastric, and colon cancers, is introduced along with explored underlying molecular mechanisms. Expert commentary: Though CSC ablation is still in the empirical stages and not in clinical practice, several strategies for ablating CSCs in GI cancers had been published, proton-pump inhibitors (PPIs) that regulate the membrane-bound ABC transporters, which underlie drug resistance; chloroquine (CQ) that inhibits autophagy, which is responsible for tumor survival; Hedgehog/Wnt/Notch inhibitors that influence the underlying stem-cell growth, and some natural products including Korean red ginseng, cancer-preventive kimchi, Artemisia extract, EGCG from green tea, and walnut extracts.
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| [41] |
The transcription factor signal transducers and activators of transcription 3 (STAT3) can promote cancer metastasis, but its underlying regulatory mechanisms in gastric cancer cell invasiveness still remain obscure. We investigated the relationship between STAT3 and glycogen synthase kinase-3beta (GSK-3beta) and its significance in metastatic potential in gastric cancer cells. Immunohistochemical tissue array analysis of 267 human gastric carcinoma specimens showed that the expressions of active forms of STAT3 (pSTAT3) and GSK-3beta (pGSK-3beta) were found in 68 (25%) and 124 (46%) of 267 gastric cancer cases, respectively, showing a positive correlation (p < 0.001). Cell culture experiments using gastric cancer cell lines SNU-638 and SNU-668 revealed that STAT3 suppression did not affect pGSK-3beta expression, whereas GSK-3beta inhibition reduced pSTAT3 expression. With respect to metastatic potential in gastric cancer cells, both STAT3 suppression and GSK-3beta inhibition decreased cell migration, invasion, and mesenchymal marker (Snail, Vimentin, and MMP9) expression. Moreover, the inhibitory effects of STAT3 and GSK-3beta on cell migration were synergistic. These results demonstrated that STAT3 and GSK-3beta are positively associated and synergistically contribute to metastatic potential in gastric cancer cells. Thus, dual use of STAT3 and GSK-3beta inhibitors may enhance the efficacy of the anti-metastatic treatment of gastric cancer.
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| [42] |
Tumor necrosis factor (TNF)-alpha-inducing protein (Tipalpha) is a newly identified carcinogenic factor secreted by Helicobacter pylori (H. pylori). Although it has been proved that Tipalpha is a strong inducer of epithelial-mesenchymal transition (EMT), a crucial process of migration, the exact molecular mechanism is unknown. Current evidence indicates that the oncogenic transcription factor signal transducers and activators of transcription 3 (STAT3) is inappropriately activated in multiple malignancies, including gastric cancer. In this study, we showed that Tipalpha significantly down-regulated the expression of EMT-related markers E-cadherin as well as up-regulated N-cadherin and vimentin in SGC7901 cells, with typical morphological changes of EMT. Tipalpha also promoted proliferation and migration of SGC7901 cells. Furthermore, Tipalpha activated interleukin-6 (IL-6)/STAT3 signaling pathway in SGC7901 cells. The effects of Tipalpha treatment observed was abolished when we block IL-6/STAT3 signaling pathway. Altogether, our data demonstrated that Tipalpha may accelerate tumor aggressiveness in gastric cancer by promoting EMT through activation of IL-6/STAT3 pathway.
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| [43] |
As a cancer stem cell marker, CD44 variant 6 (CD44v6) has been implicated in carcinogenesis, tumor progression, and metastasis in a variety of human carcinomas. However, little is known about the expression of CD44v6 in Gastric Carcinoma (GC). Therefore we investigated CD44v6 expression in clinical specimen and further explore the underlying molecular mechanisms.In this study, we systemically investigated CD44v6 expression by immunohistochemistry in normal, premalignant gastric mucosa (low and high grade intraepithelial neoplasia), and GC at various stages. The correlation of CD44v6 expression with clinicopathological characteristics, and prognosis in GC was also analyzed. Next, we investigated cell proliferation, migration and invasion in GC cell lines. Furthermore, we explored a novel mechanism by which CD44V6 was upregulated in GC cell.The immunohistochemistry results showed that enhanced expression of CD44v6 was closely associated with tumor differentiation, lymph node metastasis, TNM stage and poor prognosis in GC patients. In gastric cancer cell lines, CD44v6 involved in cell proliferation, invasion and metastasis in Next, report on a novel mechanism by which interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling up-regulates expression of CD44v6. RNA interference silencing of STAT3 resulted in decrease of CD44v6 levels. We also found that STAT3 inhibitor AG490 decrease expression of CD44v6 by blocking activation of STAT3, even in the presence of IL-6. Targeting STAT3-mediated CD44v6 up-regulation may represent a novel, effective treatment by eradicating the stomach tumor microenvironment.
[本文引用:1]
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| [44] |
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| [45] |
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| [46] |
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| [47] |
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| [48] |
Recently, two epidemiological studies showed that long-term treatment with proton pump inhibitors (PPIs) increased the risk of gastric cancer. It is well known that hypergastrinemia predisposes to gastric neoplasia in animals as well as man. Recently a study showed that hypergastrinemic patients had an increased risk of gastric cancer when followed for about 25 years. It is likely that hypergastrinemia is the pathogenic factor for gastric carcinogenesis due to PPI. PPI are the only group of drugs that causes long-term hypergastrinemia in the doses used in a clinical setting. Due to the likely carcinogenic effect, PPIs should be used carefully. Moreover, since the carcinogenic effect of Helicobacter pylori (Hp) infection also may be mediated by an increase in gastrin, Hp should be eradicated whenever treatment with PPI is initiated. In peptic ulcer disease Hp eradication is the treatment of choice. Gastro-oesophageal reflux disease (GERD) is the most prevalent condition leading to long-term use of inhibitors of gastric acid secretion. Only in severe oesophagitis should the treatment be initiated by PPIs, whereas histamine-2 (H-2) blockers ought to be the initial option in most cases of GERD particularly since PPI treatment induces tolerance to H-2 blockers. In the cases where long-term PPI treatment is necessary, the dose should be adjusted by the determination of chromogranin A, which in a way reflects 24-h gastrin exposure. Finally, due to latency of neoplasia, the use of PPI must be very restricted in children and young adults.
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| [49] |
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