肥胖与大肠腺瘤关系的临床及分子机制

目的:初步了解肥胖人群患大肠腺瘤的危险性,并进一步深入探讨肥胖与大肠肿瘤的关系及其防治.方法:选择2006-12/2007-12在我院行结肠镜检查的患者539例,分为大肠腺瘤组(n=250)和正常对照组(n=289),测量身高、体质量、腰围及臀围,利用多因素Logistics/归进行相关性分析;从大肠腺瘤组中选择4例病理为管状腺瘤或绒毛管状腺瘤的大肠息肉组织,2例BMI＞24kg/m2,WC＞85 cm;2例BMI＜24kg/m2,WC＜85 cm,进行信号通路功能芯片基因筛查.结果:肥胖或腹型肥胖(以BMI和WC划分)患大肠腺瘤的调整后OR值分别为2.48(95%CI:1.19.5.20,P=0.016)和1.75(95%CI:1.15-2.66,P=0.009),其中男性调整后的OR值分别为4.10(95%CI:1.26-13.31,P=0.019)和1.70(95%CI:1.00-2.88,P=0.019),以BMI划分的超重组差异无统计学意义;以WHR划分的腹型肥胖在各种分析中均无统计学意义.基因芯片杂交结果显示,两组差异表达的基因共23个,其中BMI＞24 kg/m2组比BMI＜24 kg/m2组表达上调有6个,下调有17个,脂肪细胞因子Foxa2表达上调,IL-8和Leptin滚达下调.结论:肥胖或腹型肥胖与大肠腺瘤的发生存在显著相关性,肥胖男性的患病风险明显大于女性;患大肠腺瘤肥胖人群的腺瘤组织中存在一些异常表达的因子.     

Survivin表达与大肠肿瘤关系研究进展

大肠肿瘤的发生过程是一个经过腺瘤阶段多阶段、多基因改变的过程，随着对肿瘤发生过程分子机制研究的不断深入，癌基因和抑癌基因的失活以及细胞增殖和凋亡的失衡在大肠肿瘤的研究领域成为近年来研究的热点。survivin，又称生存素，是新近发现的一种凋亡抑制基因，越来越多的研究表明其在大肠肿瘤的发生、发展及转移中起重要作用。     

代谢综合征与大肠肿瘤的关系

我国大肠癌的发病率逐年升高，在城市地区已成为发病率最高的恶性肿瘤之一。2001年对北京市普通人群一项大肠癌筛检工作中，28．35％患者检出大肠息肉，其中腺瘤性息肉占67％，反映北京城区人群中大肠腺瘤的发病率相当高，这也是大肠癌在北京地区高发的原因。流行病学资料、临床、动物实验研究结果均表明，大肠腺瘤、大肠癌发病原因与环境因素密不可分，如肥胖、缺乏锻炼、低纤维素饮食、糖尿病、高脂血症等，上述危险因素均与代谢综合征密切相关。虽然代谢综合征与大肠肿瘤发病相关已受到注意，但远未受到重视，相关研究文献远少于大肠肿瘤其他方面的研究。以下对有关研究进行综述。     

肥胖及其相关癌症研究进展

超重居全世界所有疾病负担的第6位,据估计全世界有11亿人超重,其中1/3是肥胖,并且1/10的儿童肥胖[1].20世纪80～90年代肥胖人群显著增加,体重指数(BMI)增加了3个单位,即增加了9 kg,而平均身高仅增加了2 cm.     

大肠肿瘤基因筛检方法研究进展

大肠肿瘤的发生发展是一种多步骤多基因改变的分子生物学模型。肿瘤组织向肠腔排出的肿瘤细胞很可能对大肠液中多种降解酶产生抵抗作用，因而可保持其ＤＮＡ的稳定性。利用以ＰＣＲ技术为基础的分子生物学检查方法，可快速准确检出特异基因位点的改变，为粪便基因筛检方法奠定了基础。     

大肠肿瘤化学预防的研究进展

环氧合酶（ＣＯＸ）是花生四烯酸代谢的限速酶,存在两种同功酶：ＣＯＸ－１和ＣＯＸ－２。ＣＯＸ－２是炎症过程中的一个重要的诱导酶,在肿瘤的形成与发展过程中起一定的作用。ＣＯＸ－２选择性抑制剂的开发和应用,已成为非甾体类抗炎药（ＮＳＡＩＤｓ）发展的热点,有望成为大肠肿瘤的化学预防剂。其中Ｇｅｌｅｃｏｘｉｂ已于１９９８年１２月被美国食品与药品管理局批准上市,成为目前市场上第一个ＣＯＸ－２选择性抑制剂。     

肥胖与心血管病变——从流行病学到发病机制

大量流行病学和临床研究证实随着体质指数（BMI）和腰围（Wc）的增加，疾病的危险性也随之增加，肥胖相关疾病主要包括心血管病（CVD）、高血压、2型糖尿病（T2DM）和血脂紊乱等。早在1994年美国心脏协会（AHA）首先在其网站提出对成年人进行体重控制的建议，1997年WHO明确宣布肥胖是一种疾病，同年AHA发表了有关肥胖与CVD的声明，1998年AHA又提出肥胖是冠心病（CHD）的主要危险因素，要求采取行动控制肥胖。1999年AHA正式提出与肥胖相关的糖尿病是一种CVD。进入2000年后，AHA及美国国立心肺及血液研究所（NHLBI）对肥胖的关注程度骤然增加，几乎每年均有肥胖与CVD的专题讨论和声明发布。2001年AHA又将肥胖列入其长期重点研究资助领域，2002年美国国立卫生研究所（NIH）又发布了肥胖研究的中长期战略规划，2004年AHA发表了肥胖与心脑血管病的执行总结，     

大肠肿瘤基因筛检方法研究进展

大肠肿瘤的发生发展是一种多步骤多基因改变的分子生物学模型。肿瘤组织向肠腔排出的肿瘤细胞很可能对大肠液中多种降解酶产生抵抗作用,因而可保持其DNA的稳定性。利用以PCR技术为基础的分子生物学检查方法,可快速准确地检出特异基因位点的改变,为粪便基因筛检方法奠定了基础。     

大肠癌发病机制基础研究进展与展望

大肠癌是严重危害人民健康的恶性肿瘤之一,因为发病机制尚未完全阐明而造成诊断和治疗上的困难是其发病率、死亡率居高不下的重要原因之一。大肠癌发病机制包括遗传、环境等诸多因素,目前大概有20%的患者有家族遗传史,其余则为散发性大肠癌。本文将从大肠癌癌变的分子机制、干细胞在大肠癌发生中的作用、炎症相关的大肠癌三个方面来阐述大肠癌发病机制的研究进展与临床应用前景,并不包括遗传性大肠癌。     

体质量指数与结直肠癌相关性的研究现状

结直肠癌(colorectal cancer,CRC)是消化系统常见的严重危害人们健康的杀手,全球每年约有120万新发病例,其中中国约有13万.随着我国社会经济发展和饮食结构的改变,CRC的发病率和死亡率呈逐年上升趋势,且平均发病年龄低于西方国家约20岁,居所有恶性肿瘤中的第2位,在中国发达地区已经接近西方发达国家.CRC的发病是多种因素综合作用的结果,近四分之一的CRC患者可以通过良好的生活习惯来避免患病.目前全球有2/3的成年人正在与超重和肥胖做斗争.近期大量研究表明,高体质量指数(body mass index,BMI)与结直肠癌的发病具有一定关系.本文就BMI与CRC相关性的研究现状作一综述.     

结直肠癌与肥胖等多种病因学的关系探讨

目的肥胖被证实为增加结直肠癌发病风险的重要因素。本研究探讨BMI与结直肠癌发病的关系,为结直肠癌的预防提供参考。 方法选取泰安市中心医院及泰山医学院附属医院202例首次确诊的结直肠癌患者和202名非癌症患者,分析比较两组患者BMI情况。 结果首次确诊的结肠癌患者平均身体质量指数（body mass index,BMI）为25.1±3.5 kg/m²,对照组人群平均BMI为21.2±3.1 kg/m²,结直肠癌患者的BMI明显高于健康对照人群（t=-12.153,P<0.001）。结肠癌患者的BMI与健康对照组比较,在性别（P<0.05）、是否胆囊炎或胆囊切除病史（P<0.05）方面差异均有统计学意义。Logistic回归分析示,BMI值（t=12.171,P<0.001）、有胆囊炎或胆囊切除病史者（t=3.128,P=0.002）及性别（t=3.321,P=0.001）与结直肠癌的发病呈显著正相关关系,和是否糖尿病（t=1.260,P=0.208）及年龄（t=-1.790,P=0.074）与结直肠癌的发病不相关。 结论结直肠癌的发生与BMI情况、是否患有胆囊病者和性别有关。     

间质化与结直肠癌相关性的研究进展

上皮间质化（epithelial-mesenchymal transition,EMT）,指上皮细胞在某些特定因素下获得间质细胞表型的过程。在恶性肿瘤的发生和进展过程中EMT发挥重要作用。结直肠癌细胞的侵袭运动和肿瘤远处转移与EMT密切相关,EMT可能成为未来抑制结直肠癌转移的一个新的靶点,为肿瘤治疗开辟一个新方向。     

Association of visceral obesity and early colorectal neoplasia

AIM:To examine whether visceral adipose tissue(VAT)serves as a risk factor for colorectal adenoma-early colorectal cancer(CRC)sequence.METHODS:A retrospective case-control study was conducted with 153 patients with stageⅠCRC,age/sex-matched 554 patients with colorectal adenoma and557 normal controls.All subjects underwent various laboratory tests,abdominal fat computed tomography(CT),and colonoscopy.VAT was defined as an intraabdominal adipose tissue area measured by CT scan.Adipose tissue area was measured at the level of the umbilicus from CT scan.We used the lowest quartile of VAT and subcutaneous adipose tissue area as a reference group.RESULTS:The body mass index(BMI),total cholesterol,fasting glucose and VAT areas were significantly different among normal,adenoma and CRC groups.The VAT area was 120.6±49.0 cm2in normal controls,130.6±58.4 cm2in adenoma group and 117.6±51.6cm2in CRC group(P=0.002).In univariate analysis,increased BMI was a risk factor for CRC compared to control(P=0.025).However,VAT area was not a risk factor for CRC compared to control.In multivariate analysis that adjusted for smoking,alcohol consumption and subcutaneous adipose tissue area,VAT area was inversely related to CRC,compared to the adenoma(OR=0.53,95%CI:0.31-0.92,highest quartile vs lowest quartile).CONCLUSION:Our study shows that visceral obesity is not a risk factor for early CRC.Visceral obesity might influence the normal-adenoma sequence but not the adenoma-early carcinoma sequence.     

Association between obesity-related adipokines and colorectal cancer:A case-control study and meta-analysis

AIM:To examine the association between obesityrelated adipokines(adiponectin,leptin,resistin,interleukin-6(IL-6),and tumor necrosis factor-α(TNF-α)and colorectal cancer(CRC)risk.METHODS:Serum levels of adipokines were measured in 100 CRC patients and age-and sex-matched controls for the data analysis.Unconditional logistic regression models were used for estimating ORs and95%CIs related to each adipokine.For the metaanalysis,studies published before July 2013 available on Medline/PubMed and EMBASE were retrieved.The analysis included a total of 17 relevant studies(including the present case-control study):nine studies on adiponectin and eight on leptin.The effect sizes of ORs and 95%CIs were estimated using RevMan 5.1.Heterogeneity was evaluated using Cochran’s Q-test and I2 statistics.RESULTS:Among the five adipokines,only resistin levels were significantly higher in cases than in controls(P<0.001).The case-control study results showed no association between adiponectin and CRC and a negative association between leptin and CRC.However,the results of the meta-analysis showed a significant inverse association between adiponectin and CRC(OR=0.91,95%CI:0.83-1.00,P=0.04)and no association between CRC and leptin.After stratification by study design,an inverse association between adiponectin and CRC was observed in prospective studies only(OR=0.90,95%CI:0.82-0.99,P=0.03),whereas the association between leptin and CRC was inconsistent(prospective studies:OR=1.14,95%CI:1.02-1.27,P=0.02 and retrospective studies:OR=0.47,95%CI:0.29-0.74,P=0.001).The associations of resistin and TNF-αwith CRC risk were positive,but no association was observed for IL-6.CONCLUSION:Our results suggest a negative association of leptin,positive associations of resistin and TNF-α,and null associations of adiponectin and IL-6with CRC.However,further studies with larger number of prospective approaches are needed.     

糖尿病与结直肠癌患病危险关系的调查分析

目的:了解糖尿病(DM)与结直肠癌患病的关系,明确糖尿病相关因素对结直肠癌发病的影响.方法:采用病例对照的方法分析同时期住院的结直肠癌(n=364)与非肿瘤患者(n=733)与糖尿病相关因素的关系及差异.对比分析两组患者的糖尿病患病情况、糖尿病家族史、结直肠癌家族史、并发病情况、吸烟、饮酒等生活行为以及血脂水平等方面的差异.结果:结直肠癌组糖尿病患者患结直肠癌的危险度是非糖尿病患者的1.72倍,有糖尿病家族史者患结直肠癌的危险度也明显增加(OR=1.64);有结直肠癌家族史的糖尿病患者患结直肠癌的风险度(OR=3.23)高于无结直肠癌家族史的糖尿病患者(OR=1.57);但通过进一步分层分析表明无论患者有无结直肠癌家族史,结直肠癌组糖尿病患者所占比例均高于对照组.多因素回归分析显示:年龄、性别、糖尿病家族史、冠心病、高血压、吸烟、饮酒及血脂对结直肠癌没有显著影响;糖尿病及结直肠癌家族史对结直肠癌患病具有显著影响(OR=2.99,P＜0.01;OR=1.79,P＜0.01).结论:糖尿病与结直肠癌患病存在一定的相关性,糖尿病增加了患结直肠癌的风险性,其是结直肠癌患病的独立危险因素.     

代谢综合征与大肠癌相关性研究

目的探讨代谢综合征与大肠癌的相关性。方法采用病例对照的方法分析同时期住院的大肠癌患者及非肿瘤患者与代谢综合征的相关因素及差异。对比分析两组患者的体质指数（BMI）、空腹血糖（FBG）、血脂、糖尿病患病率、高血压患病率等方面的差异。结果大肠癌组代谢综合征的患病率明显高于对照组（P=0.000,OR=1.915）。随着代谢综合组分在个体聚集越多,患大肠癌的可能性越大。多因素Logisitc回归分析显示,高血压、血脂、空腹血糖对大肠癌没有显著影响,糖尿病、BMI为大肠癌发病的独立危险因素（OR=1.127,P〈0.05;OR=2.738,P〈0.05）。结论代谢综合征与大肠癌发生密切相关。BMI、糖尿病是大肠癌患病的独立危险因素,积极控制代谢综合征各危险因素对预防大肠癌患病和改善预后有重要作用。     

The obesity gene and colorectal cancer risk: a population study in Northern Italy

Background

Representing the second cause of cancer-related death after lung cancer in men and breast cancer in women, colorectal cancer (CRC) is a major health problem in Italy. Obesity is reckoned to favor CRC; however, the underlying mechanisms are unclear. Recently, a single nucleotide polymorphism (SNP) in the fat mass and obesity associated (FTO) gene was found to be significantly associated with obesity.

Aims

To establish whether the FTO SNP rs9939609 may represent a risk factor for CRC and adenoma in the Italian population.

Patients and methods

1,037 subjects were enrolled in the study and divided in 3 groups: CRC (341 pts., M/F = 197/144, mean age = 65.17 ± 11.16 years), colorectal adenoma (385 pts., M/F = 247/138, mean age = 62.49 ± 13.01 years), healthy controls (311 pts., M/F = 150/161, mean age = 57.31 ± 13.84 years). DNA was extracted from whole blood, and stored frozen for rs9939609 genotyping by real-time PCR.

Results

The frequency of the obesity-associated mutated A allele (AA+AT) on the FTO gene was 69.77% among controls, and 71.85% and 65.71% respectively among CRC and polyp patients. Compared to control subjects the AA+AT genotype had no significant effect on the risk for either CRC (OR = 1.106; CI 95% = 0.788-1.550; p = 0.561) or colorectal adenomas (OR = 0.830; CI 95% = 0.602-1.144; p = 0.255). We did not observe any association between the AA genotype and CRC/polyp localization and age at diagnosis. As measured in a patient subset, carriership of the risk alleles did not reflect in a significantly altered BMI.

Conclusion

The obesity-linked FTO variants do not play a significant role in modulating the colorectal cancer risk in the Italian population.     

Wait times from presentation to treatment for colorectal cancer: A population-based study

BACKGROUND:

The wait time from cancer diagnosis to treatment has been a recent focus of cancer care in Canada.

OBJECTIVE:

To examine the trends in wait times from patient presentation to treatment (overall health system wait time [OWT]) for colorectal cancer (CRC).

METHODS:

Patients with colorectal adenocarcinomas, diagnosed between 2001 and 2005, and their first definitive treatments were identified from the population-based Manitoba Cancer Registry (Winnipeg, Manitoba). By linkage to Manitoba Health and Healthy Living’s administrative databases, a patient’s first gastrointestinal investigation (abdominal radiological imaging, lower gastrointestinal endoscopy or fecal occult blood test) before CRC diagnosis was identified. The index contact with the health care system was estimated from the date of the visit with the physician who ordered the first gastroenterological investigation. The OWT was defined as the time from the index contact to the first treatment, while diagnostic delay was defined as the time from the index contact to the diagnosis of CRC. Multivariate Cox regression analysis was performed to determine independent predictors of OWT.

RESULTS:

The OWT was estimated for 2552 cases of CRC over the five years that were examined. The median OWT increased from 61 days in 2001 to 95 days in 2005 (P<0.001). Most of the increase was in diagnostic wait times (median of 44 days in 2001 versus 64 days in 2005 [P<0.001]). Year of diagnosis, older age, urban residence and diagnosis at a teaching facility were independent predictors of OWT.

CONCLUSIONS:

The OWT from presentation to treatment of CRC in Manitoba steadily increased between 2001 and 2005, mostly due to diagnostic delays.