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.     

肥胖与癌症关系的研究进展

研究发现，与肥胖相关的体重指数、腰臀比的增高，胰岛素抵抗，胰岛素样生长因子-Ⅰ、胰岛素样生长因子结合蛋白-1及性激素结合球蛋白水平的改变，瘦素水平升高及其受体基因变异等与绝经后乳腺癌、上消化道癌、大肠癌、妇科肿瘤、恶性淋巴瘤等发生、发展明显相关。其发病机制可能因肥胖导致高胆固醇和高胰岛素血症，致使体内免疫细胞的活性受到抑制和功能下降。改变不合理的饮食结构和生活行为，加强锻炼保持正常体重可以预防和控制一些相关癌症的发生和发展。     

饮食与肥胖及相关癌症的研究进展

据世界卫生组织(WHO)估计,全世界有11亿人超重,其中1/3是肥胖,并且儿童人数的1/10是儿童肥胖[1].上世纪60年代初,肥胖还未成为流行病学问题,但在之后的30年肥胖显著增加,80~90年代体重指数(BMI)增加了3个单位,即增加了9 kg,但平均身高仅增加了2 cm[2].     

肥胖是癌症的种子

21位世界著名科学家用5年的时间综合评估了17种癌症与肥胖的关系。这次新发布的报告明确指出，肥胖能够增加患食管癌、胰腺癌、结直肠癌、肾癌和绝经后的乳腺癌的危险。[编者按]     

腹型肥胖在胰岛素抵抗中的作用

腹型肥胖即中心性肥胖是多种疾病包括2型糖尿病、心血管疾病、高血压以及某些癌症发生的高危因子。早在2005年4月IDF就给出代谢综合征（MS）全球定义，将中心性肥胖作为其诊断的一个必要条件，并提出以腰围作为衡量指标。第19届世界糖尿病大会声明：由内脏脂肪堆积形成的中心性肥胖是胰岛素抵抗（IR）的标志。是形成代谢综合征（MS）的基石。现在又有学者提出把代谢综合征新定义为“中心性肥胖综合征”可能更为适合。     

腹型肥胖在胰岛素抵抗中的作用

腹型肥胖即中心性肥胖是多种疾病包括2型糖尿病、心血管疾病、高血压以及某些癌症发生的高危因子。早在2005年4月IDF就给出代谢综合征（MS）全球定义，将中心性肥胖作为其诊断的一个必要条件，并提出以腰围作为衡量指标。第19届世界糖尿病大会声明：由内脏脂肪堆积形成的中心性肥胖是胰岛素抵抗（IR）的标志。是形成代谢综合征（MS）的基石。现在又有学者提出把代谢综合征新定义为“中心性肥胖综合征”可能更为适合。     

肥胖和肥胖基因

本文综述了肥胖的生理调节，肥胖基因的克隆、分子序列、突变及其基因产物－肥胖蛋白的结合特征与生物学效应，分析了应用肥胖蛋白作为治疗肥胖新途径的前景。     

肥胖与癌症的相关性现代看法

肥胖是目前威胁全世界人民健康素质的重大公共卫生问题。有研究统计分析2005年全球超重人群约有93700万,肥胖人群约有39600万,照此趋势,至2030年,预计超重和肥胖人群将占到全球总人口的58%左右。     

肥胖和肥胖基因

本文综述了肥胖的生理调节，肥胖基因的克隆、分子序列、突变及其基因产物－肥胖蛋白的结构特征与生物学效应，分析了应用肥胖蛋白作为治疗肥胖新途径的前景。     

肥胖增加人体患癌病的危险

<正> 加利福利亚大学的圣地亚哥卡烈(MichaelKarin)称,医生总是担心我们的体重,因为超重和肥胖会引发心血管疾病和Ⅱ型糖尿病,要知道这2种疾病都可以用现有的药物控制好。但是,我们也应该担心肥胖可增加癌症的风险,因为癌症的发生往往防治上更     

Obesity and breast cancer screening

BACKGROUND: Compared to normal weight women, women with obesity have higher mortality from breast cancer but are less often screened. OBJECTIVES: To examine the relation between mammography use and weight category and to examine the influence of race, illness burden, and other factors on this relationship. DESIGN AND SETTING: The 1998 National Health Interview Survey, a U.S. civilian population-based survey. PARTICIPANTS: Five thousand, two hundred, and seventy-seven women ages 50 to 75 years who responded to the Sample Adult and Prevention questionnaires. MEASUREMENTS: Mammogram use in the preceding 2 years. RESULTS: Among 5277 eligible women, 72% reported mammography use. The rate was 74% among white women and 70% among black women. Among white women, mammogram use was lowest in women with a body mass index (BMI) greater than 35 kg/m(2) (64% to 67%). After adjusting for sociodemographic factors, health care access, medical conditions, hospitalizations, and mobility status, higher BMI was associated with lower screening among white women, P =.02 for trend; the relative risk (RR) for screening in moderately obese white women (BMI, 35 to 40 kg/m(2)) was 0.83 (95% confidence interval [CI], 0.68 to 0.96) compared to normal weight white women. Compared to normal weight black women, mammography use was similar or higher in overweight (BMI, 25 to 30 kg/m(2); RR, 1.19; 95% CI, 1.01 to 1.32), mildly obese (BMI, 30 to 35 kg/m(2); RR, 1.22; 95% CI, 0.98 to 1.39), and moderately obese black women (RR, 1.37; 95% CI, 1.37 to 1.50) after adjustment. The P value for the race-BMI interaction was.001. Results for white and black women were unchanged after additional adjustment for psychological functioning and health habits. CONCLUSION: Among white women, those with higher BMI were less likely to undergo breast cancer screening than normal weight women. This relationship was not seen in black women. Our findings were not explained by differences in sociodemographic factors, health care access, illness burden, or health habits. More research is needed to determine the reasons for these disparities so that appropriate efforts can be made to improve screening.     

Obesity and thyroid cancer: epidemiologic associations and underlying mechanisms

The incidence of thyroid cancer has been rising over the past few decades along with a parallel increase in obesity. Observational studies have provided evidence for a potential association between the two. By contrast, clinical data for a link between type 2 diabetes mellitus, a condition strongly associated with obesity, and thyroid cancer are limited and largely not supportive of such an association. Obesity leads to hypoadiponectinemia, a pro‐inflammatory state, and insulin resistance, which, in turn, leads to high circulating insulin and insulin‐like growth factor‐1 levels, thereby possibly increasing the risk for thyroid cancer. Thus, insulin resistance possibly plays a pivotal role in underlying the observed association between obesity and thyroid cancer, potentially leading to the development and/or progression of thyroid cancer, through its interconnections with other factors including insulin‐like growth factor‐1, adipocytokines/cytokines and thyroid‐stimulating hormone. In this review, epidemiological and clinical evidence and potential mechanisms underlying the proposed association between obesity and thyroid cancer risk are reviewed. If the association between obesity and thyroid cancer demonstrated in observational studies proves to be causal, targeting obesity (and/or downstream mediators of risk) could be of importance in the prevention and management of thyroid cancer.     

Obesity, adipocytokines, and insulin resistance in breast cancer

The adipocytokines are biologically active polypeptides that are produced either exclusively or substantially by the adipocytes, and act by endocrine, paracrine, and autocrine mechanisms. Most have been associated with obesity, hyperinsulinaemia, type 2 diabetes, and chronic vascular disease; in addition, six adipocytokines--vascular endothelial growth factor, hepatocyte growth factor, leptin, tumour necrosis factor-alpha, heparin-binding epidermal growth factor-like growth factor, and interleukin-6--promote angiogenesis while one, adiponectin, is inhibitory. Obesity and insulin resistance have both been identified as risk factors for breast cancer and are associated with late-stage disease and poor prognosis. Angiogenesis is essential for breast cancer development and progression, and so it is plausible that obesity-related increases in adipocytokine production and a reduction in adiponectin may adversely affect breast cancer outcome by their angiogenesis-related activities. There is also experimental evidence that some adipocytokines can act directly on breast cancer cells to stimulate their proliferation and invasive capacity. Thus, adipocytokines may provide a biological mechanism by which obesity and insulin resistance are causally associated with breast cancer risk and poor prognosis. Both experimental and clinical studies are needed to develop this concept, and particularly in oestrogen-independent breast cancers where preventive and therapeutic options are limited.     

Obesity and prognosis of breast cancer

Obesity has a complicated relationship to both breast cancer risk and the clinical behaviour of the established disease. It is suggested that obesity is associated with both an increased risk of developing breast cancer risk and worse prognosis after disease onset. In post-menopausal women, various measures of obesity such as body mass index, weight, weight gain and waist : hip ratio have all been positively associated with risk of developing breast cancer. In most but not all case-control and prospective cohort studies, an inverse relationship has been found between weight and breast cancer among pre-menopausal women. Some data suggest that adult weight gain and central obesity increase the risk of pre-menopausal breast cancer. Obesity at the time of diagnosis is thought to be significant as a poor prognostic factor. Obesity is associated with adverse outcomes in both pre- and post-menopausal women with breast cancer. Many cancer survivors seek ways to minimize the risk of recurrence and death because of breast cancer. Despite complex and at times controversial data, enough evidence is available at present to suggest that weight management should be a part of the strategy to prevent the occurrence, recurrence and death because of breast cancer. In this review the effect of obesity on the prognosis of breast cancer is examined in detail.     

Obesity: epidemiology and clinical aspects

At the beginning of the 21st Century, obesity has become the leading metabolic disease in the World. So much so, that the World Health Organisation refers to obesity as the global epidemic. In fact, obesity is a common disease affecting not only affluent societies but also developing countries. Currently 300 million people can be considered as obese and, due to the rising trend in obesity prevalence, this figure could double by year 2025 if no action is taken against this threat. In terms of health impairment, the importance of obesity lies in the fact that, besides being a disease in itself, it is a risk for many other diseases, mainly from the metabolic and cardiovascular area. Among these, type 2 diabetes, dyslipemia, hyperuricemia, arterial hypertension and cardiovascular disease are the most frequent. Also, respiratory diseases such as obesity hypoventilation syndrome and obstructive sleep apnoea syndrome are strongly associated with obesity.     

Obesity, the PI3K/Akt signal pathway and colon cancer

Obesity is currently reaching epidemic levels worldwide and is a major predisposing factor for a variety of life-threatening diseases including diabetes, hypertension and cardiovascular diseases. Recently, it has also been suggested to be linked with cancer.
Epidemiological studies have shown that obesity increases the risk of colon cancer by 1.5–2 fold with obesity-associated colon cancer accounting for 14–35% of total incidence. Several factors, altered in obesity, may be important in cancer development including increased levels of blood insulin, insulin-like growth factor I, leptin, TNF-α, IL-6 as well as decreased adiponectin. A unifying characteristic of all these factors is that they increase the activity of the PI3K/Akt signal pathway. The PI3K/Akt signal pathway in turn activates signals for cell survival, cell growth and cell cycle leading to carcinogenesis. Here we review the evidence that PI3K/Akt and its downstream targets are important in obesity-associated colon cancer and thus, that targeted inhibition of this pathway could be employed for the prevention of obesity-associated colon cancer and incorporated into the therapy regime for those with irremovable colon cancers.     

Obesity and outcomes in patients treated with chemoradiotherapy for esophageal carcinoma

Body mass index (BMI) is a risk factor for comorbid illnesses and cancer development. It was hypothesized that obesity status affects disease outcomes and treatment‐related toxicities in esophageal cancer patients treated with chemoradiotherapy (CRT). From March 2002 to April 2010, 405 patients with non‐metastatic esophageal carcinoma at MD Anderson Cancer Center treated with either definitive or neoadjuvant CRT were retrospectively analyzed. Patients were categorized as either obese (BMI ≥ 25 kg/m²) or nonobese (BMI < 25 kg/m²). Progression‐free survival and overall survival times were examined using the Kaplan–Meier method and Cox proportional hazards regression analysis. One hundred fifteen (28.4%) patients were classified as nonobese and 290 (71.6%) as obese. Obese patients were more likely than others to have several comorbid diseases (P < 0.001), adenocarcinoma located distally (P < 0.001), and have undergone surgery (P = 0.004). Obesity was not associated with either worse operative morbidity/mortality (P > 0.05) or worse positron emission tomography tumor response (P = 0.46) on univariate analysis, nor with worse pathologic complete response (P = 0.98) on multivariate analysis. There was also no difference in overall survival, locoregional control, or metastasis‐free survival between obese and nonobese patients (P = 0.86). However, higher BMI was associated with reduced risk of chemoradiation‐induced high‐grade esophagitis (P = 0.021), esophageal stricture (P < 0.001), and high‐grade hematologic toxicity (P < 0.001). In esophageal cancer patients treated with CRT, obesity is not predictive of poorer disease outcomes or operative morbidities; instead, data suggest it may be associated with decreased risk of acute chemotherapy‐ and radiotherapy‐related treatment toxicities.     

Obesity drugs and their targets: correlation of mouse knockout phenotypes with drug effects in vivo

Sequencing of the human genome has yielded thousands of potential drug targets. The difficulty now is in determining which targets have real therapeutic value and should be the focus of a drug discovery effort. The available evidence suggests that knockout technology can be used prospectively to identify targets that are amenable to drug development for the treatment of a variety of diseases. This review compares the knockout phenotypes of 21 potential obesity targets with the effects of therapeutics designed for those targets on rodents and, when data were available, on humans. The phenotypes of obesity target knockouts model the effects seen when therapeutics designed for those obesity targets are delivered to rodents; of the 21 obesity targets reviewed, 16 showed a correspondence between knockout phenotype and drug effect in mice and/or rats. This suggests that, at least in terms of evaluating obesity targets, it is rare for compensatory developmental changes caused by the gene knockout to prevent detection of the relevant phenotype. In the majority of cases, the knockout phenotypes also modelled the effects seen when the relevant therapeutics were delivered to humans. Thus, it seems rational to use mouse knockout technology prospectively to identify genes that regulate body fat in vivo, and then to develop anti-obesity therapeutics by targeting the human protein products of these genes. Ultimately, the value of using this approach to identify novel targets for human anti-obesity therapies will be judged by future studies examining the anti-obesity effect, in humans, of the therapeutics that result from this approach.