脂联素及其受体在肥胖相关的乳腺癌中的作用

肥胖指脂肪组织在体内异常或过度的蓄积。它影响着女性常见的恶性肿瘤之一乳腺癌的发生、发展及治疗效果和预后。脂肪组织可产生多种细胞因子,其中脂联素在肥胖相关的乳腺癌中发挥着重要作用。流行病学研究表明,血浆或血清脂联素水平与肥胖相关的乳腺癌的关系受患者月经状态、乳腺癌家族史、体质指数等因素的影响。脂联素对乳腺癌的作用主要体现在阻止细胞增殖和促进细胞凋亡、参与肿瘤细胞的血管化、影响乳腺癌细胞的侵袭性等方面。进一步明确脂联素在肥胖相关的乳腺癌中的作用机制,有可能为乳腺癌的预防或治疗提供一个新的突破口。     

脂联素与肿瘤相关关系的研究现状

脂联素是由脂肪细胞特异分泌的一种生物活性分子,与肥胖、胰岛素抵抗等多种疾病相关。近几年关于脂联素与乳腺癌、子宫内膜癌、子宫平滑肌瘤、白血病、结肠直肠癌、胃癌、前列腺癌等几种恶性肿瘤的相关关系及其作用机制的研究取得了较大的进展。     

脂联素与肿瘤相关关系的研究现状

脂联素是由脂肪细胞特异分泌的一种生物活性分子，与肥胖、胰岛素抵抗等多种疾病相关。近几年关于脂联素与乳腺癌、子宫内膜癌、子宫平滑肌瘤、白血病、结肠直肠癌、胃癌、前列腺癌等几种恶性肿瘤的相关关系及其作用机制的研究取得了较大的进展．     

血清脂联素水平与肿瘤关系的实验研究

目的：探讨脂联素作为血清学标志物在肿瘤诊断和治疗中的价值。方法：用酶联免疫吸附试验对292例不同肿瘤患者和60名健康人血清中脂联素水平进行检测。结果：正常男女之间血清脂联素水平无差别;60名乳腺癌患者血清平均脂联素水平明显低于30名健康女性平均血清脂联素水平,66名结肠癌患者血清平均脂联素水平明显低于60名健康对照者,胃癌患者血清中脂联素水平与正常人血清脂联素水平无明显差别;肝癌和肺癌患者血清脂联素平均水平略高于正常人,但无统计学意义。结论：乳腺癌和结肠癌患者血清脂联素低于正常人;肝癌、肺癌、胃癌患者体内脂联素与正常人无明显差别。循环系统中低水平脂联素可能是某些肿瘤的危险因素。     

脂联素与肿瘤相关性的研究进展

脂肪组织已经不是普通意义上的脂肪仓库,而成为一个内分泌器官。脂肪细胞分泌的众多脂肪因子当中,脂联素(adiponectin)是惟一一个随着脂肪组织体积变大在血液循环中浓度反而降低的因子。脂联素不但在糖类和脂类代谢过程中起到重要作用,目前也认为和一些恶性肿瘤有关。大量的临床试验和基础研究表明,肿瘤患者血清脂联素水平偏低,并且肿瘤细胞表达脂联素受体。因此,脂联素可能通过与脂联素受体结合并激活受体和信号传导通路的下游,直接作用于肿瘤细胞,或者通过抗血管生成,诱导肿瘤细胞凋亡和其他机制调节细胞增殖,从而导致肿瘤的发生。通过研究脂联素,可以发现肥胖和肿瘤之间的关系。     

脂联素及其受体与子宫内膜癌关系的研究进展

脂联素是脂肪细胞分泌的一种内源性细胞因子,与肥胖相关疾病如子宫内膜癌等密切相关.子宫内膜癌患者血清中脂联素呈低水平状态.脂联素通过其受体参与糖脂代谢、抗炎、抗肿瘤等生理过程.本文就脂联素及其受体的基因结构、生物学作用、其作用于子宫内膜癌的相关机制做一论述.     

脂联素对肿瘤新生血管的作用

 脂联素是由脂肪组织特异分泌的一种细胞因子,在糖代谢和脂类代谢中起着重要作用,在与肥胖相关恶性肿瘤的发生发展中也起着重要的作用。目前的研究对脂联素对肿瘤血管的作用仍有很大分歧,本文讨论脂联素对肿瘤新生血管的作用,提示其作为肿瘤血管抑制剂的应用前景。     

肥胖脂肪因子与食管腺癌的研究进展

肥胖与肿瘤是全球两大影响健康的重要问题,肥胖增加食管腺癌的发病及死亡风险。脂肪组织能够分泌多种生物学活性的脂肪因子,如瘦素、脂联素、抵抗素等。近年研究发现脂肪因子在胃食管返流病、Barrett食管及癌变中发挥重要作用。本文就肥胖及脂肪因子与食管腺癌的研究进展进行综述。     

脂联素受体的表达与大肠癌分期和分级的关系

 目的
探讨脂联素受体表达水平与大肠癌病理学分级、临床分期间的关系。方法应用免疫组织化学SP法检测 71例大肠癌
组织、20例大肠腺瘤和71例大肠正常黏膜组织中脂联素受体的表达情况,以Image-Pro Plus图像分析软件进行半定
量测定。结果脂联素受体在大肠癌中低表达,其表达水平和大肠癌的Dukes分期、淋巴结转移和病理学分级密切相
关。肿瘤的Dukes分期越晚、淋巴结发生转移者及分化程度越低,其脂联素受体的阳性表达率越低,表达程度越差
。健康对照组、腺瘤组中脂联素受体均匀表达于大肠黏膜组织腺管的腺胞细胞膜及细胞质;腺癌组中脂联素受体在
肿瘤细胞的细胞膜及细胞质少量表达,腺癌组与健康对照组、腺瘤组比较差异均具有统计学意义(P均＜0.005）,
健康对照组与腺瘤组比较差异无统计学意义(P>0.05）,其中脂联素受体在健康对照组的阳性表达率明显高于腺癌
组(98.59% vs.74.65%脂联素受体1和97.18% vs.70.42%脂联素受体2）,在Dukes分期、肿瘤的病理学分级及有无淋
巴结转移间的比较差异也具有统计学意义(P<0.05）。结论脂联素的表达水平降低与大肠癌及其分化水平、Dukes分
期和淋巴结转移具有一定的负相关关系,它有望成为临床上治疗和监测大肠癌的重要手段之一。     

人脂联素重组体体外对乳腺癌细胞侵袭和转移的抑制

目的：研究人脂联素重组体对人乳腺癌MDA—MB-231细胞体外侵袭能力的影响。方法：将MDA—MB-231细胞分设对照组和脂联素重组体加药（2．5、5、0、10、20、30μg／ml）组，药物作用一定时间后，分别以MTT法、Transwell小室实验，Chamber小室实验，黏附实验检测脂联素重组体对乳腺癌细胞增殖、侵袭、迁移和黏附能力的影响，以明胶酶谱法检测其对肿瘤细胞分泌MMP-2和MMP-9的影响。结果：脂联素重组体质量浓度高于5．0μg／ml时，对MDA—MB-231细胞生长具有明显的抑制作用（P〈0．01）；能明显地降低肿瘤细胞体外侵袭能力（P〈0．01），侵袭抑制率随脂联素重组体质量浓度的升高而增加，介于22．64％～77．84％之间；脂联素重组体质量浓度高于2．5μg／ml时，明显地抑制肿瘤细胞的迁移能力（P〈0．01）；脂联素重组体对ECM和FN黏附能力影响的程度不同，对FN的敏感性大于ECM；脂联素重组体质量浓度大于2．5μg／ml时，明显抑制肿瘤细胞MMP-2和MMP-9的分泌（P〈0、05或P〈0．01），后者的分泌量随质量浓度的升高而下降。结论：脂联素重组体在大于2．5μg／ml时，可能通过保护基底膜不受破坏而抑制人乳腺癌细胞的侵袭能力。     

Equol,Adiponectin, Insulin Levels and Risk of Breast Cancer

Breast cancer is one of the most frequently diagnosed cancers and the leading cause of cancer death among women. Soy isoflavones have been widely studied and among all isoflavones equol has been gaining interest with regard to its relationship with breast cancer risk. Obesity has been revealed as one of the breast cancer risk factors, known to be associated with high levels of circulating insulin and decreased levels of adiponectin. Hence there have been many studies investigating relationships between insulin and adiponectin levels and breast cancer risk. Additionally recent findings have suggested that insulin and adiponectin themselves may have influence on breast cancer development, independent of obesity. In the present review, we discuss the relationships between breast cancer risk and equol, insulin and adiponectin levels, which are three important factors in our ongoing hospital-based case-control study. Herein these factors are reviewed not only from the clinical viewpoint but also from possible chemical and biological points of view which may explain clinical observations.     

肥胖与乳腺癌关系的研究进展

乳腺癌目前已成为全球女性最常见的恶性肿瘤之一,其发病率和死亡率在女性恶性肿瘤中位居第二。大量临床研究和流行病学资料已证实肥胖与乳腺癌的发生、发展密切相关,其发病机制可能涉及雌激素、胰岛素、胰岛素样生长因子-1（IGF-1）、瘦素、脂联素、炎症因子等多种肥胖相关因子。近年来的研究对肥胖促进乳腺癌发展的机制进行了深入分析,并进一步了解到肥胖对乳腺癌的诊断结果、肿瘤特点、治疗以及预后可产生重要影响。因此,控制体重可能是预防复发转移的积极措施,维持正常体重有助于乳腺癌的防治。     

Obesity and breast cancer: status of leptin and adiponectin in pathological processes

It is well recognized that obesity increases the risk of various cancers, including breast malignancies in postmenopausal women. Furthermore, obesity may adversely affect tumor progression, metastasis, and overall prognosis in both pre- and postmenopausal women with breast cancer. However, the precise mechanism(s) through which obesity acts is/are still elusive and this relationship has been the subject of much investigation and speculation. Recently, adipose tissue and its associated cytokine-like proteins, adipokines, particularly leptin and adiponectin, have been investigated as mediators for the association of obesity with breast cancer. Higher circulating levels of leptin found in obese subjects could be a growth-enhancing factor as supported by in vitro and preclinical studies, whereas low adiponectin levels in obese women may be permissive for leptin’s growth-promoting effects. These speculations are supported by in vitro studies which indicate that leptin promotes human breast cancer cell proliferation while adiponectin exhibits anti-proliferative actions. Further, estrogen and its receptors have a definite impact on the response of human breast cancer cell lines to leptin and adiponectin. More in-depth studies are needed to provide additional and precise links between the in vivo development of breast cancer and the balance of adiponectin and leptin.     

Adiponectin and breast cancer

Adiponectin, an adipose tissue-derived hormone, has been studied intensively for the past decade because of its anti-inflammatory, anti-atherogenic, and anti-diabetic properties. Recent advances suggest that adiponectin also plays an important role in the development and progression of various cancers, especially obesity-related cancers. In this review, the authors focus on the potential role of adiponectin in breast cancer, an obesity- and endocrine-associated tumor. Epidemiological studies have shown that plasma adiponectin level is a risk factor for breast cancer in post-menopausal women. Adiponectin and its receptors are expressed on both breast cancer line cells and tumor tissues. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. Underlying mechanisms include the inhibition of cell proliferation and promotion of apoptosis, the regulation of tumorigenic-related factors, and the suppression of angiogenesis. The signaling pathways linking adiponectin with tumorigenesis might provide potential drug targets for the future. However, more convincing evidence is needed to fully elucidate the exact role of adiponectin in breast cancer, since both its beneficial effects and possible mechanisms remain controversial.     

肥胖与乳腺癌

肥胖被证实是乳腺癌等恶性肿瘤的危险因素之一。大量流行病学资料显示肥胖与乳腺癌的发生发展密切相关,其发病机制可涉及雌激素、胰岛素、瘦素、脂联素、炎症因子等肥胖相关因子。因此,维持正常体重可能有助于乳腺癌的防治。     

肥胖与乳腺癌

 肥胖被证实是乳腺癌等恶性肿瘤的危险因素之一。大量流行病学资料显示肥胖与乳腺癌的发生发展密切相关,其发病机制可涉及雌激素、胰岛素、瘦素、脂联素、炎症因子等肥胖相关因子。因此,维持正常体重可能有助于乳腺癌的防治。     

Variants of the adiponectin and adiponectin receptor 1 genes and breast cancer risk

Breast cancer risk is higher among obese women and women with diabetes. Adiponectin is a protein exclusively secreted by adipose tissue, circulating levels of which have been associated with breast cancer risk. Whether genetic variants within the adiponectin pathway are associated with breast cancer risk is unknown. To explore the association of genetic variants of the adiponectin (ADIPOQ) and adiponectin receptor 1 (ADIPOR1) genes with breast cancer risk, we conducted a case control study of female patients with breast cancer and healthy female controls from New York City recruited between 1999 and 2004. We genotyped 733 hospital-based breast cancer cases and 839 controls for 10 haplotype-tagging single nucleotide polymorphisms (SNP) of ADIPOQ and ADIPOR1. Two ADIPOQ SNPs (rs2241766 and rs1501299), which have been associated with circulating levels of adiponectin, were associated with breast cancer risk [rs1501299*GG: odd ratios (OR), 1.80; 95% confidence interval (95% CI), 1.14-2.85; rs2241766*TG: OR, 0.61; 95% CI, 0.46-0.80]. One ADIPOR1 SNP (rs7539542), which modulates expression of adiponectin receptor 1 mRNA, was also associated with breast cancer risk (OR, 0.51; 95% CI, 0.28-0.92). Based on the known function of rs2241766 and rs1501299, we categorized individuals by adiponectin signaling status and found that, when compared with high signalers, intermediate signalers had a 4.16-fold increase in breast cancer risk (95% CI, 0.49-35.19), and low signalers had a 6.56-fold increase in breast cancer risk (95% CI, 0.78-54.89; P(trend) = 0.001). This is the first report of an association between functionally relevant variants of the adiponectin pathway and breast cancer risk. The results warrant further studies of the adiponectin pathway in breast cancer.     

Molecular mechanisms of leptin and adiponectin in breast cancer

Obesity is associated with an increased risk of breast cancer in postmenopausal women. Accumulating evidence suggests that adipose tissue, which is an endocrine organ producing a large range of factors, may interfere with breast cancer development. Leptin and adiponectin are two major adipocyte-secreted hormones. The pro-carcinogenic effect of leptin and conversely, the anti-carcinogenic effect of adiponectin result from two main mechanisms: a modulation in the signalling pathways involved in proliferation process and a subtle regulation of the apoptotic response. This review provides insight into recent findings on the molecular mechanisms of leptin and adiponectin in mammary tumours, and discusses the potential interplay between these two adipokines in breast cancer.     

Adiponectin mediates an antiproliferative response in human MDA-MB 231 breast cancer cells

Numerous epidemiological studies have documented that obesity is a risk factor for breast cancer especially in post-menopausal women. However, the molecular basis of this association is not well known. In contrast to leptin, plasma levels of adiponectin, another major adipokine, are decreased in obese subjects. Therefore, we and others hypothesized that adiponectin may be a paracrine factor negatively controlling mammary tumor development. We recently demonstrated growth inhibition of the estrogen-sensitive breast cancer MCF-7 cell line by adiponectin. The purpose of the present study was to determine whether this anti-proliferative effect of adiponectin also applies to the MDA-MB 231 estrogen-insensitive breast epithelial cancer cell line. Our results demonstrate that i) the adiponectin-specific receptors AdipoR1 and R2 are expressed in these cells, and ii) the subphysiological concentrations of recombinant adiponectin inhibit MDA-MB 231 cell growth and concomitantly enhance the expression of Bax and p53, two pro-apoptotic genes. Moreover, the invalidation of AdipoR1 and R2 mRNA experiments demonstrated that the anti-proliferative and pro-apoptotic effects of adiponectin were partially mediated via AdipoR1 and R2. We describe, for the first time, that AdipoR mRNA expression was down-regulated by adiponectin and leptin in MDA-MB 231 cells. Taken altogether, these results strongly suggest that the two adipokines should be considered as i) additional factors of breast cancer risk, and ii) may therefore be potential targets in breast cancer therapy.     

Associations between adiponectin and two different cancers: breast and colon

Objectives: Breast and colon cancer are neoplasms well known to be related to obesity. Adiponectin, a proteinthat increases in obesity, seems to be involved in the relationship but clinical data are limited. Methods: In thisstudy, we therefore evaluated the serum adiponectin levels in 87 breast and 27 colon cancer patients and assessedthe relation with BMI, menopausal status, receptor status and stage of disease. Results: Serum adiponectin levelswere lower in cancer cases (8583 ± 2095 ng/ml for breast cancer, 9513 ± 2276 for colon cancer) than in controls(13905 ± 3263). Conclusion: A low serum adiponectin level may be associated with both breast and colon cancer,and that this association is not statistically significant for either receptor or menopausal status in breast cancergroups.