前列腺干细胞抗原与前列腺癌

人们对前列腺癌早期诊断的标志物及理想的治疗靶点的探寻从未停止过脚步。迄今为止,一批潜在的将用于诊治前列腺癌的候选蛋白逐步浮现。其中一个新发现的重要的生物标志物是前列腺干细胞抗原（PSCA）。PSCA是一种糖化磷脂酰肌醇（GPI）锚定的细胞膜表面糖蛋白,属于Thy-1/Ly-6家族成员之一,在人前列腺癌细胞中高表达,在正常前列腺组织中表达有限。正是这样的组织特异性,使其成为前列腺癌诊断和预后判断的一个潜在的标志物和颇具吸引力的免疫治疗的候选靶点。研究显示,PSCA表达的增加与前列腺癌Gleason评分、肿瘤分期和骨转移均具有相关性。PSCA作为前列腺癌特异的膜抗原,具有严格的表达模式,现其已被作为免疫治疗的靶点而进行深入研究,如利用单克隆抗体、结合细胞毒的抗体、遗传工程T细胞、PSCA疫苗和负载肽段的树突状细胞（DC）等手段进行免疫治疗。本文主要对PSCA在前列腺癌诊断、预后判断、治疗等方面的研究加以综述,同时简要介绍一些PSCA在其他肿瘤中与在前列腺癌中表达情况不同的研究报告。     

Minimally invasive surgery for upper gastrointestinal cancer: Our experience and review of the literature

Minimally invasive surgery(MIS) for upper gastro-intestinal(GI) cancer, characterized by minimal access, has been increasingly performed worldwide. It not only results in better cosmetic outcomes, but also reduces intraoperative blood loss and postoperative pain, leading to faster recovery; however, endoscopically enhanced anatomy and improved hemostasis via positive intracorporeal pressure generated by CO2 insufflation have not contributed to reduction in early postoperative complications or improvement in long-term outcomes. Since 1995, we have been actively using MIS for operable patients with resectable upper GI cancer and have developed stable and robust methodology in conducting totally laparoscopic gastrectomy for advanced gastric cancer and prone thoracoscopic esophagectomy for esophageal cancer using novel technology including da Vinci Surgical System(DVSS). We have recently demonstrated that use of DVSS might reduce postoperative local complications including pancreatic fistula after gastrectomy and recurrent laryngeal nerve palsy after esophagectomy. In this article, we present the current status and future perspectives on MIS for gastric and esophageal cancer based on our experience and a review of the literature.     

前列腺干细胞抗原在人前列腺癌组织中的表达及意义

目的 探讨前列腺干细胞抗原（PSCA）在人前列腺癌（PCa）和正常前列腺（NP）、良性前列腺增生（BPH）组织中的表达及其与临床分期、病理分级的关系。方法 采用免疫组织化学（IHC）链霉菌过氧化物酶法（SP法）检测26例人PCa石蜡包埋标本、10例BPH患者的前列腺切除标本及3例NP标本中PSCA的表达。结果 PSCA在PCa组织中表达阳性率为96．2％，其中强阳性率为88．5％。NP组织阳性率为66．7％（均为弱阳性）。BPH组织阳性率为70．0％（均为弱阳性）。PCa与NP、BPH组织表达水平差异有显著性意义（P〈0．01），BPH与NP组织表达水平无统计学意义（P〉0．05）。PSCA在PCa组织主要表达于癌细胞，细胞间质和肌肉组织均无表达；NP及BPH组织表达则定位于前列腺上皮的基底细胞层。PSCA表达水平与PCa临床分期、病理分级均无相关性（P〉0.05）。结论 PSCA是一个新的细胞表面抗原，可能在PCa的诊断、免疫治疗等方面具有广阔的应用前景。     

Common single nucleotide polymorphisms in the vascular endothelial growth factor gene and colorectal cancer risk

Purpose Tumor growth requires the formation of new blood vessels, a phenomenon known as angiogenesis. The most important regulator of angiogenesis is vascular endothelial growth factor (VEGF). Several common polymorphisms in the VEGF-gene have been associated with different VEGF expression, production and plasma levels according to allele status, and influence the risk of developing different types of cancer. Therefore, these variants might be risk factors for colorectal cancer (CRC). Methods In the present case–control study, VEGF genotypes of the +936 C > T, −2578 C > A and −634 G > C polymorphisms were determined in 427 patients with histologically verified CRC and 427 age and sex-matched healthy control subjects. Genotypes were analyzed by a fluorogenic exonuclease assay (TaqMan™). P-value for age at diagnosis was analyzed by student’s t test, P-values for tumor characteristics were determined by Pearson’s Chi-square test. Threshold for significance was P < 0.05. Results At the time of diagnoses, patients were between 29 and 83 years of age, with a mean age of 61 ± 10.9 years. VEGF −2578 C > A and VEGF −634 G > C genotype frequencies were similar among patients and controls. Carriers of the 936T-allele were found slightly more frequent among controls (27.2%) than among patients (22.5%), but this difference did not reach statistical significance (P = 0.07). Furthermore, no correlation was found between all these variants and tumor characteristics like size, histological grading, positive regional lymph node metastases or tumor stage. Conclusion We conclude that the investigated polymorphisms are not associated with individual susceptibility to colorectal cancer.     

前列腺癌组织中前列腺干细胞抗原的表达及与前列腺特异性抗原的关系

目的 探讨前列腺癌组织中前列腺干细胞抗原(PSCA)表达及与前列腺特异抗原(PSA)的关系.方法 采用免疫组织化学染色法检测63例前列腺癌组织标本PSCA的表达,引入阳性灰度值概念判定染色强度;分析PSCA表达水平与临床分期、血清PSA及游离PSA和总PSA比值的关系. 结果 63例中,A、B、C、D期分别为8例、13例、22例和20例,其前列腺癌组织中PSCA表达的平均阳性灰度值分别为24.53灰阶(Gs)、43.16 Gs、59.37 Gs和75.29 Gs,PSCA表达与肿瘤临床分期呈正相关(P＜0.01),与患者血清PSA无相关性(P＞0.05),与游离PSA和总PSA比值呈负相关(P＜0.01).结论 PSCA可作为判断前列腺癌浸润程度及预后的指标之一.     

Genetic contribution to motility disorders of the upper gastrointestinal tract

Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.     

Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes

Background

Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D.

Methods

Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean ± SD = 57 ± 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors.

Results

During the mean follow-up period of 8.5 ± 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08–1.65); P = 6.7 × 10⁻³ under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01–1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65–1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12–1.39); P = 4.8 × 10⁻⁵). The adjusted cancer risk was 2.41 (95% C.I. 1.23–4.69) for patients with four risk alleles comparing to patients without risk allele.

Conclusions

T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes.

Impact

Our findings provide novel insights into the pathogenesis of cancer in diabetes.     

Genetic susceptibility and gastric cancer risk: The importance of meta-analyses as a statistical tool

Gastric cancer (GC) is a complex disease and a worldwide health burden due to its high prevalence and poor prognosis. A deeper knowledge of the factors involved in the development and progression of GC could help to identify subpopulations at risk that therefore require surveillance or early treatment strategies. Current research is based on the study of genetic variants that confer a higher risk of GC and their interactions with environmental exposure. Recently, meta-analysis has emerged as an important statistical method involving pooling of data from individual association studies to increase statistical power and obtain more conclusive results. Given the importance of chronic inflammation in the process of gastric carcinogenesis, the present article reviews the most recent meta-analyses of the contribution of cytokine gene polymorphisms to GC risk.     

上皮-间质转化与肿瘤转移及干细胞的研究进展

肿瘤细胞的侵袭、转移及干性特征是患者治疗失败、预后差的主要原因。为了给肿癌患者治疗提供一种新的治疗方案,从分子水平来解释肿瘤细胞的侵袭、转移及干性特征至关重要。最近的研究表明上皮-间质转化(epithelial-mesenchymal transition,EMT)对肿瘤细胞的侵袭、转移及干性特征起到举足轻重的作用。EMT 可使上皮性肿瘤细胞获得间充质细胞表型,在增强肿瘤细胞的侵袭和转移能力的同时,也使得肿瘤细胞具有自我更新等干细胞特性。本综述阐明 EMT 与肿瘤转移及干细胞的相互关系及其调控机制,有望为肿瘤的靶向治疗开辟新思路。     

β_2-肾上腺素能受体基因多态性与新疆维吾尔族患者支气管哮喘间的关系研究

目的 :探讨 β2 肾上腺素能受体 (β2 adrenergicreceptor,β2 AR) 16 ,2 7位点基因多态性与新疆维吾尔族支气管哮喘患者及其临床表型间的关系。方法 :采用序列特异引物聚合酶链反应 (sequencespecificprimers polymerasechainreaction ,SSP PCR)技术检测 12 3例维吾尔族哮喘组患者β2 AR16和 2 7位点基因多态性 ,并与 89例正常组进行对照 ,统计分析 β2 AR16和 2 7位点基因型与哮喘病情严重度的关系。应用UniCAP变应原检测系统 (SWEDENPHARMACIAUniCAPSystems)测定血清嗜酸性粒细胞阳离子蛋白(ECP)、血清总免疫球蛋白E(T IgE)和特异性IgE抗体 (Phadiatop)水平肺功能测定 ,记录 1s用力呼气容量占预计值百分比 (FEU1 % )及最大峰流速 (PEF)。结果 :新疆维吾尔族人群 β2 AR基因 16位点多态性分布以杂合子所占比率较高 ;2 7位点多态性分布以纯合子所占比率较高 ;16 ,2 7位点多态性分布频率与北方汉族人群不同。亦与英、美高加索人群不同。Gly16纯合子基因型的频率在哮喘组明显高于正常对照组的频率 (13 0 1%vs 10 11% ,P <0 0 5 ) ,而且在夜间哮喘组的频率较非夜间哮喘组明显增高 (30 6 %vs 14 9% ,P <0 0 1) ,β2 AR16位点基因多态性在重度哮喘组Gly Gly基因型分布频率明显高于轻度哮喘和中?     

Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract

Esophageal atresia(EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia(72%) and gastroesophageal reflux(GER)(67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients.     

A case of synchronous squamous cell carcinoma in the esophagus and stomach

Synchronous esophageal and gastric cancers with the pathologic features of a squamous cell carcinoma are extremely rare. A 57-year-old male visited our hospital with a history of hematemesis and was diagnosed with a synchronous cancer. He underwent a staging work-up, and the resectable lesion in the stomach was operated on following radiologic and endoscopic evaluations. The pathologic examination revealed a synchronous cancer consisting of squamous cell carcinoma in the distal esophagus and the cardia of the stomach. We report a case of a synchronous cancer that was successfully treated by surgical resection followed by concurrent chemoradiotherapy. We also discuss the hypothesis regarding the origin and presentation of the synchronous cancer and highlight the importance of careful surveillance by physicians at the time of diagnosis.     

Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

BACKGROUND: Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. METHODS: To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.     

Concordance of EUS and MRI/MRCP findings among high-risk individuals undergoing pancreatic cancer screening

Background/Objectives: Surveillance with endoscopic ultrasonography (EUS) and MRI/magnetic retrograde cholangiopancreatography (MRCP) is recommended for individuals at high risk for pancreatic cancer. We sought to characterize the findings of these surveillance exams and define the level of concordance between these two modalities.Methods173 asymptomatic high-risk individuals (HRIs) meeting criteria for pancreatic cancer surveillance underwent EUS, MRI/MRCP, or both between 2008 and 2021. Clinical records were reviewed in all cases.ResultsHRIs underwent an average of 3.6 ± 3.2 surveillance exams over a period of 3.3 ± 3.5 years. Abnormalities including intraductal papillary mucinous neoplasms (IPMNs), solid lesions, and parenchymal irregularities were identified in 50.9% (n = 88). Four of these abnormalities (2.3%) had worrisome features, defined by cyst size, thickened/enhancing cyst walls, rapid growth rate, or change in main pancreatic duct diameter. All four worrisome lesions were seen on both MRI/MRCP and EUS. No pancreatic cancers were detected. Baseline EUS and MRI/MRCP exams were compared in 106 patients for concordance, and most (n = 66, 62.3%) were concordant. High levels of concordance were specifically observed for a dilated main pancreatic duct (p < 0.01) and cystic lesions >5 mm (p = 0.01). Among discordant cases, most (30/40; 75%) involved abnormal tissue heterogeneity seen primarily on EUS. None of these discordant lesions ultimately developed worrisome features.ConclusionsWorrisome pancreatic lesions were uncommon in our high-risk pancreatic cancer population and were detected by both EUS and MRI/MRCP. There was mild discordance with respect to less worrisome findings, but these discrepancies were not associated with any adverse clinical outcomes.     

Genetic variations in the SMAD4 gene and gastric cancer susceptibility

AIM:To explore the association between mothers against decapentaplegic homolog 4 (SMAD4) gene polymorphisms and gastric cancer risk.METHODS:Five tagging single nucleotide polymor-phisms (tSNPs) in the SMAD4 gene were selected and genotyped in 322 gastric cancer cases and 351 cancerfree controls in a Chinese population by using the polymerase chain reactionrestriction fragment length polymorphism method.Immunohistochemistry was used to examine SMAD4 protein expression in 10 normal gastric tissues adjacent to...     

Liver cancer stem cell markers: Progression and therapeutic implications

Cancer stem cells(CSCs) are a small subpopulation in cancer, have been proposed to be cancer-initiating cells, and have been shown to be responsible for chemotherapy resistance and cancer recurrence. The identification of CSC subpopulations inside a tumor presents a new understanding of cancer development because it implies that tumors can only be eradicated by targeting CSCs. Although advances in liver cancer detection and treatment have increased the possibility of curing the disease at early stages, unfortunately, most patients will relapse and succumb to their disease. Strategies aimed at efficiently targeting liver CSCs are becoming important for monitoring the progress of liver cancer therapy and for evaluating new therapeutic approaches. Herein, we provide a critical discussion of biological markers described in the literature regarding liver cancer stem cells and the potential of these markers to serve as therapeutic targets.     

Bile acids as endogenous etiologic agents in gastrointestinal cancer

Bile acids are implicated as etiologic agents in cancer of the gastrointestinal （GI） tract, including cancer of the esophagus, stomach, small intestine, liver, biliary tract, pancreas and colon/rectum. Deleterious effects of bile acid exposure, likely related to carcinogenesis, include： induction of reactive oxygen and reactive nitrogen species; induction of DNA damage; stimulation of mutation; induction of apoptosis in the short term, and selection for apoptosis resistance in the long term. These deleterious effects have, so far, been reported most consistently in relation to esophageal and colorectal cancer, but also to some extent in relation to cancer of other organs. In addition, evidence is reviewed for an association of increased bile acid exposure with cancer risk in human populations, in specific human genetic conditions, and in animal experiments. A model for the role of bile acids in GI carcinogenesis is presented from a Darwinian perspective that offers an explanation for how the observed effects of bile acids on cells contribute to cancer development.