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。     

脂肪因子与结直肠癌

脂联素、瘦素、网膜素、内脂素均为脂肪组织细胞分泌的脂肪因子,与肥胖、胰岛素抵抗密切相关.研究发现上述脂肪因子也与结直肠癌的发生发展密切相关,有望成为结直肠癌临床诊断以及预后判断的生物学标志物.目前关于脂肪因子如何诱发结直肠癌的机制尚不清楚,仍需开展深入的研究.     

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。     

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。     

脂肪因子对肿瘤代谢调节作用的研究进展

肿瘤组织中普遍存在代谢的改变,涵盖糖代谢、脂代谢和氧化还原平衡等多个方面。肥胖导致的脂肪因子失衡,如瘦素、内脂素和抵抗素的升高以及脂联素的降低,是肥胖相关肿瘤发生发展的关键因素之一,在肿瘤代谢的改变中也发挥一定的作用。了解各种脂肪因子在肿瘤代谢中的作用,有利于阐明肿瘤的发生发展机制,以及探索肿瘤临床诊治的新思路。      

脂肪细胞与肿瘤转移的关系研究进展

肥胖是威胁人们健康的主要慢性疾病之一,主要由脂肪组织扩增引起。在人体,脂肪组织是一个动态的内分泌器 官,负责能量稳态。过度肥胖通常会导致代谢紊乱、类固醇激素分泌改变、慢性亚临床炎症以及增加多种肿瘤的发病风险。肿 瘤细胞与脂肪细胞的微环境之间存在密切关系,一方面,脂肪细胞来源的细胞因子,如趋化因子配体 2、白介素⁃6、肿瘤坏死因 子 α、瘦素和脂联素等,可通过激活不同的信号通路促进肿瘤的侵袭转移能力;脂肪细胞来源的游离脂肪酸及脂滴可通过 FABP4、CD36等转运蛋白转移到肿瘤细胞中,提高肿瘤β氧化速率,产生大量能量,促进肿瘤细胞分裂增殖;另一方面,脂肪细 胞可使Treg细胞、CD8+ 细胞毒性T细胞、巨噬细胞发生代谢重编程,促进Treg细胞及M2型巨噬细胞增殖,抑制CD8+ 细胞毒性T 细胞杀肿瘤活性,从而导致肿瘤免疫逃逸;使中性粒细胞重编程,破坏血管内皮细胞的黏附,导致血管壁渗透性增加,有利于肿 瘤细胞穿过血管壁,转移到远处。本文主要探究脂肪细胞与肿瘤转移的关系,旨在为肿瘤治疗提供新的靶点。     

肿瘤相关脂肪微环境与肿瘤的恶性发展

肿瘤周围脂肪组织可通过激素、脂肪因子及脂肪酸等生物活性分子与肿瘤细胞产生复杂“对话”,并在肿瘤增殖、侵袭及转移等恶性事件中扮演重要角色。伴随肿瘤发展演化,肿瘤周围脂肪组织在原有结构及功能基础上,发生了丰富而复杂的变化。本文新提出“肿瘤相关脂肪微环境”的概念,并对肿瘤相关脂肪微环境的构成、特点及成因进行分析,进一步探讨其在不同肿瘤恶性进程中的可能作用,以期为靶向肿瘤相关脂肪微环境抗肿瘤药物的开发及临床应用提供理论支持。     

脂肪因子在肿瘤治疗中的研究进展

肥胖是多种肿瘤发生的高危因素, 在肥胖促进肿瘤发生、发展的过程中, 脂肪组织分泌的脂肪因子扮演着重要的角色。不同的脂肪因子通过其各自的信号通路发挥着促癌或抑癌作用。调整生活方式控制体质量或者靶向脂肪因子及其受体, 是肿瘤治疗领域的一大研究方向, 但目前多数因子还处于基础研究及临床前研究阶段, 有关各种脂肪因子促癌或抑癌的分子机制还待进一步探索, 同时双重抑制剂及联合疗法是未来脂肪因子用于肿瘤治疗的重点研究策略。     

Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors

The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17β-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17β-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells.     

Cholesterol-induced mammary tumorigenesis is enhanced by adiponectin deficiency: role of LDL receptor upregulation

Adiponectin is an adipokine that can suppress the proliferation of various human carcinoma cells. Although its anti-tumor activities have been suggested by many clinical investigations and animal studies, the underlying mechanisms are not fully characterized. In MMTV-polyomavirus middle T antigen (MMTV-PyVT) transgenic mice models, reduced- or complete loss-of-adiponectin expression promotes mammary tumor development. The present study demonstrated that while tumor development in control MMTV-PyVT mice is associated with a progressively decreased circulating cholesterol concentration, adiponectin deficient MMTV-PyVT mice showed significantly elevated total- and low density lipoprotein (LDL)-cholesterol levels. Cholesterol contents in tumors derived from adiponectin deficient mice were dramatically augmented. High fat high cholesterol diet further accelerated the tumor development in adiponectin deficient PyVT mice. The protein levels of LDL receptor (LDLR) were found to be upregulated in adiponectin-deficient tumor cells. In human breast carcinoma cells, treatment with LDL-cholesterol or overexpressing LDLR elevates nuclear beta-catenin activity and facilitates tumor cell proliferation. On the other hand, adiponectin decreased LDLR protein expression in breast cancer cells and inhibited LDL-cholesterol-induced tumor cell proliferation. Both in vivo and in vitro evidence demonstrated a stimulatory effect of adiponectin on autophagy process, which mediated the down-regulation of LDLR. Adiponectin-induced reduction of LDLR was blocked by treatment with a specific inhibitor of autophagy, 3-methyladenine. In conclusion, the study demonstrates that adiponectin elicits tumor suppressive effects by modulating cholesterol homeostasis and LDLR expression in breast cancer cells, which is at least in part attributed to its role in promoting autophagic flux.     

Adiponectin与肿瘤

adiponectin作为脂肪细胞分泌的一种多肽激素,在肿瘤发生中起着重要的抑制作用,它主要是通过与血管发生的相关活性负调控肿瘤的发生发展,并通过结合某些肿瘤细胞中的adiponectin受体或者激活其下游信号通路而直接作用于肿瘤细胞。鉴于adiponectin抑制血管生成的特性以及启动caspase家族诱导细胞凋亡的作用,有望成为一种新的肿瘤治疗药物。     

Decreased adiponectin level is associated with aggressive phenotype of tongue squamous cell carcinoma

Circulating adiponectin levels are inversely associated with risk of various obesity‐related cancers. However, the effect of adiponectin on carcinogenesis and progression of tongue squamous cell carcinoma (TSCC) remains unknown. We measured serum adiponectin levels in 59 patients with TSCC and 50 healthy controls. Expression of adiponectin and its receptors in paired tumor and paracancerous specimens were determined by immunohistochemical staining (n = 37) and western blot (n = 30), respectively. Serum adiponectin level was lower in patients than in controls (5.0 ± 2.4 vs 8.4 ± 3.5 μg/mL, P < 0.01), and was inversely associated with histological grade and lymph node metastasis but not tumor size. Local adiponectin levels in tumor tissue gradually decreased as tumor‐node‐metastasis stage increased, while the expression of adiponectin receptors was unchanged. In addition, serum adiponectin levels in the TSCC patients without metabolic and cardiovascular diseases, or without smoking and drinking habits, were still lower than in controls. Furthermore, adiponectin inhibited the migration, but not proliferation, of SCC15 cells in vitro. These results indicate that a decreased adiponectin level is associated with risk of TSCC. Hypoadiponectinemia might be used as a biomarker to predict an aggressive phenotype of TSCC.     

Adiponectin effects on human breast cancer cells are dependent on 17-beta estradiol

Adiponectin, an adipocyte-derived serum protein, is known to positively affect the glucose and lipid metabolism and these effects are mediated by its receptors, AdipoR1 and R2. Serum adiponectin levels are inversely associated with breast cancer risk, but the molecular mechanisms underlying this association are not fully elucidated. Thus, the purpose of this study was to investigate the influence of adiponectin on breast cancer cells in vitro. We were able to demonstrate the expression of AdipoR1 and R2 in MCF-7, MDA-MB-231 and SK-BR-3 breast cancer cells on the mRNA level. Furthermore, the AdipoR1 protein could be detected by immunoblot analysis. In MCF-7 breast cancer cells, the expression of AdipoR1 significantly declined after stimulation with 17-beta estradiol, whereas the cyclin A2 expression significantly increased. Both effects were inhibited by the addition of adiponectin. Treatment with different concentrations of adiponectin in steroid-hormone-free medium did not affect cell proliferation or apoptosis. In contrast, after the addition of 17-beta estradiol, adiponectin slightly decreased the growth of the MDA-MB-231 and SK-BR3 cells but increased proliferation of the hormone-dependent MCF-7 breast cancer cells. Adiponectin also triggered cellular apoptosis in MDA-MB-231 breast cancer cells in the presence of 17-beta estradiol. These findings suggest that a cross-talk between adiponectin and estrogen receptor signaling exists in breast cancer cells and that adiponectin effects on the growth and apoptosis of breast cancer cells in vitro are dependent on the presence of 17-beta estradiol.     

Demonstration of adiponectin receptors 1 and 2 mRNA expression in human breast cancer cells

Recently, we have shown that low adiponectin levels are significantly associated with an increased breast cancer risk. It seems to be very important to study the expression of adiponectin receptor 1 (AdipoR1) and receptor 2 (AdipoR2) in the human breast epithelial cells and breast cancer cells in order to clarify whether or not adiponectin exerts its effects directly on these cells. Expression of adiponectin, AdipoR1, and AdipoR2 mRNA was determined by RT-PCR assay using the RNA samples obtained from human breast cancer cell lines (MCF-7, T47D, SKBR3, and MDA-MB231), HMEC (primary culture of normal human mammary epithelial cells), adipose tissues (axilla) as well as breast cancer cells and normal breast epithelial cells selectively collected from breast cancer tissues by laser microdissection (LMD). Adiponectin mRNA expression was observed only in the adipose tissues. On the other hand, AdipoR1 and AdipoR2 mRNA expression was observed in all four breast cancer cell lines, HMEC, adipose tissues as well as breast cancer cells and normal breast epithelial cells selectively collected by LMD. In addition, AdipoR1 and AdipoR2 expression in both normal breast epithelial cells and breast cancer cells was confirmed by immunohistochemistry. These results suggest a possibility that adiponectin might modulate the growth of normal breast epithelial cells and breast cancer cells directly through AdipoR1 and AdipoR2 receptors, and that the association of low serum adiponectin levels with a high breast cancer risk might be explained, at least in part, by the direct effect of adiponectin on the breast epithelial cells.     

Adiponectin inhibits the growth and peritoneal metastasis of gastric cancer through its specific membrane receptors AdipoR1 and AdipoR2

Adiponectin, a circulating peptide hormone produced in adipose tissue, has been shown to be reduced in the plasma of patients with cancer, suggesting that this adipokine may be mechanically involved in the pathogenesis of adiposity-related carcinogenesis. In this study, we examined the expression of adiponectin receptors (AdipoR1 and AdipoR2) and assessed the function of adiponectin in gastric cancer. All of the six gastric cancer cell lines significantly expressed mRNA and protein of both receptors with variable levels. Addition of 30 µg/mL adiponectin potently induced apoptosis and inhibited the proliferation of AZ521 and HCG27. Down-regulation of either AdipoR1 or AdipoR2 by specific siRNA significantly suppressed the growth inhibitory effects of adiponectin in both cell lines. Moreover, a local injection of adiponectin markedly inhibited the growth of AZ521 inoculated subcutaneously in nude mice. Similarly, the continuous intraperitoneal infusion of adiponectin effectively suppressed the development of peritoneal metastasis of AZ521. Adiponectin negatively regulates the progression of gastric cancer cells possibly through both AdipoR1 and AdipoR2. Although adiponectin was already reported to have antiangiogenic effects, our results suggest that the antitumor effect of adiponectin was, at least partially, dependent on the direct effects on tumor cells. ( Cancer Sci 2007; 98: 1120–1127)     

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.     

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。