生酮饮食抗肿瘤机制研究进展

生酮饮食最早用于脑部疾病的治疗,如脑胶质瘤、癫痫等。近 20 年研究表明机体内慢性炎症反应、高血糖与肿 瘤发展密切相关。运动或限制饮食可降低血糖水平、升高血酮浓度,同时降低炎症反应,而高脂、低糖的生酮饮食方式可 模拟运动或禁食产生的生理状态,这使生酮饮食用于治疗代谢性疾病成为可能。随着肿瘤代谢与肿瘤营养相关研究的不断 深入,越来越多的证据表明细胞代谢在肿瘤的发生、发展中起着非常重要的作用,加上多种新的实验手段的使用以及信号 通路研究的突破,许多研究者认为肿瘤代谢改变或许是肿瘤治疗的新靶点,因而生酮饮食用于肿瘤治疗也逐渐成为研究者 近年来关注的焦点。肿瘤细胞依赖葡萄糖作为主要能量来源,而肿瘤患者本身需要摄入更多脂肪和蛋白质,据此,提供足 够脂肪和蛋白质、限制葡萄糖的生酮饮食理论上可以治疗肿瘤。生酮饮食利用肿瘤细胞线粒体缺陷、葡萄糖依赖等特征, 通过抑制炎症、加强免疫反应、提高抗氧化应激能力、调节相关信号通路蛋白表达等多种途径抑制肿瘤生长,改善患者生 活质量,延长患者生存期,同时还能够增强放化疗的敏感性。这些机制为生酮饮食用于肿瘤治疗提供理论基础,但尚有部 分机制未完全明确,仍需进一步基础研究及临床试验证实。     

生酮饮食在肿瘤治疗中的临床应用进展

随着现代科学技术的进步和日益提高的生物化学知识水平,营养学在日常生活以及医疗中的作用开始逐步显 现。利用营养学相关知识补充或者甚至用病理学条件下的饮食控制替代药物来治疗疾病已经得以实现。此外,使用营养作 为辅助治疗方法以协同的方式增强药物效应,降低可能产生的不良反应和依赖性在众多领域中也得到了广泛证实。伴随肿 瘤细胞代谢特点的研究深入,有实验表明,肿瘤细胞共有的最重要的特征是无论在有氧还是无氧条件下均主要使用葡萄糖 （Warburg 效应）进行供能。正是由于这种特殊的代谢方式,饮食控制被认为是肿瘤治疗中的重要策略。生酮饮食是一种 高脂肪、低蛋白质和极低碳水化合物饮食方法,这种饮食的治疗机制可能潜在地影响肿瘤治疗和预后。生酮饮食治疗作为 非药物治疗的重要组成部分 , 在国内外已系统广泛应用于小儿难治性癫痫治疗中 , 并取得显著成效。虽然生酮饮食在肿瘤动 物模型实验上取得不错的效果,但临床实验研究却鲜有报道。因此,本文从生酮饮食在肿瘤治疗中的作用机制、临床应用 效果方面综述了生酮饮食对于肿瘤患者的影响 , 为肿瘤非药物治疗研究提供借鉴。     

低糖与甘露糖协同抑制胰腺肿瘤生长CSCD

目的探讨胰腺癌细胞在不同葡萄糖浓度下对甘露糖敏感度的变化与机制。方法 CCK-8细胞活性和增殖试剂盒检测在不同浓度葡萄糖与甘露糖作用下的胰腺癌细胞增殖情况,锥虫蓝染色测定细胞存活率,Western blot实验观察PMI酶表达的变化。生酮饮食联合甘露糖水溶液喂养荷瘤模型鼠验证实验结果。结果随着葡萄糖培养浓度降低,胰腺癌细胞增殖受到明显抑制,所需的甘露糖浓度也明显降低;高糖培养下甘露糖明显诱导PMI酶的表达,而在低糖下诱导效应减弱;生酮饮食具有降血糖、升血酮的作用,与甘露糖联合应用组的荷瘤鼠肿瘤抑制效果显著。结论低葡萄糖浓度增强甘露糖抑制肿瘤的作用,生酮饮食与甘露糖联合应用可提高抗肿瘤的疗效。     

肿瘤代谢重编程与营养调节对肿瘤的影响

代谢重编程是肿瘤的重要特征之一,几乎在所有的肿瘤发生、发展过程中都会被观察到。肿瘤细胞通过重编程营养物质的获取和代谢方式,来满足其对能量、生物大分子合成以及维持氧化还原平衡的需求。由于代谢重编程在肿瘤发生和发展中起到重要作用,靶向肿瘤代谢已经成为国际上抗肿瘤药物研发的热点之一。近年来,以限制特定肿瘤代谢过程为目标的营养调节作为一种新的干预手段开始被临床试验所重视,该治疗方法利用限制肿瘤特定营养来实现一系列的生物学效应,在维持正常的细胞、器官和系统功能的前提下,促进肿瘤细胞对化疗药物的敏感性。本文将对肿瘤代谢重编程在近年来的一些重要进展进行总结,也将讨论营养调节治疗的当前进展,综合讨论饮食和代谢干预在肿瘤治疗中的作用,并提供临床前和初步临床试验依据。     

肿瘤生酮代谢疗法敏感性依赖于酮体代谢酶水平

目的 基础实验及临床研究均证实KD具有一定的抗肿瘤作用,但是疗效并不一致,尚没有特异性的分子靶标或明确的适应证来衡量其抗肿瘤作用。本研究拟检测多种肿瘤细胞系酮体代谢酶的表达情况,以验证不同酮体代谢酶表达水平的肿瘤细胞对KD治疗的敏感性。方法 通过qRT-PCR检测33株肿瘤细胞系BDH1和OXCT1编码基因的表达情况。根据筛选结果选择BDH1和OXCT1高表达的HeLa细胞以及低表达PANC-1细胞进行KD敏感性的体内外验证。使用手持式细胞计数器检测含不同浓度βHB的低糖培养基中HeLa和PANC-1细胞增殖情况。然后, 敲低HeLa细胞中BDH1和OXCT1的表达水平,构建HeLa和PANC-1裸鼠皮下移植瘤, 体内外重新验证KD抗肿瘤治疗的敏感性。结果 与对照组相比,低糖组HeLa细胞和PANC-1细胞增殖明显受抑制,但是低糖培养基加入βHB后,HeLa细胞增殖明显好转,但是PANC-1细胞增殖无显著好转。动物实验中,KD显著抑制PANC-1移植瘤的生长,但是对HeLa移植瘤的生长无抑制作用,而同时敲低BDH1和OXCT1的HeLa细胞对KD治疗敏感。结论 酮体代谢关键酶BDH1和OXCT1低表达,并且无明显诱导的肿瘤对生酮代谢疗法敏感。     

雄激素受体在肿瘤中的作用及机制研究进展

雄激素受体(androgen receptor, AR)是类固醇核受体超家族的成员之一。AR在正常生理和代谢过程以及在肿瘤等多种疾病的发生与发展中起着重要作用。AR在不同肿瘤中作用不同,如在前列腺癌、黑色素瘤及胃癌等肿瘤中发挥促进作用,而在雌激素受体阳性乳腺癌中发挥肿瘤抑制作用。AR通过调节免疫(抑制肿瘤浸润性CD8⁺T细胞的活性和干性)间接发挥促进肿瘤发生发展。该文回顾并总结AR在肿瘤中的主要作用、分子机制与最新研究进展,阐明AR的研究前景,为AR的进一步研究提供思路。     

低糖增强肿瘤对二甲双胍的敏感度

目的 观察不同浓度葡萄糖对二甲双胍抗肿瘤作用的影响并探讨其作用机制。方法 在含不同浓度葡萄糖的培养基中加入二甲双胍培养细胞24 h后,检测细胞增殖情况及ATP水平。构建裸鼠皮下移植瘤,随机分成四组：正常饮食（SD）组、SD+二甲双胍（Met）组、生酮饮食（KD）组、KD+Met组,实验干预8周后,检测瘤体体积、重量以及裸鼠血糖水平。结果 培养基中葡萄糖水平≥10 mmol/L时,二甲双胍对胰腺癌细胞增殖抑制不明显,但在低糖培养基（≤5 mmol/L）中, 10mmol/L二甲双胍能明显抑制胰腺癌细胞增殖。同时,低糖培养基中各细胞ATP水平显著降低（P<0.01）。体内实验中,KD组血糖水平明显降低（P<0.01）,肿瘤生长受到显著抑制（P<0.01）。与KD组相比,KD+Met组可进一步抑制移植瘤生长（P<0.05）。结论 低糖增强肿瘤对二甲双胍的敏感度,其机制可能与减少机体ATP生成有关。     

RSF-1与肿瘤关系的研究进展及相关作用机制

重塑因子-1（Rsf-1）是位于人类染色体11q13.5区域的RSF基因的表达产物。Rsf-1是ATP依赖型染色质重塑酶中的一个亚单位,其作用为通过改变核小体的空间相对位置来影响DNA的转录情况。Rsf-1的高表达常见于卵巢癌、肝癌、肺癌、胃癌、乳腺癌、胆囊癌、膀胱癌、结直肠癌、鼻咽癌以及宫颈癌等,其表达情况往往与肿瘤大小、肿瘤分期（TMN）、耐药以及患者的预后等情况密切相关。本文总结了以往报道中关于Rsf-1在不同部位的不同肿瘤中的表达情况及意义,并对Rsf-1可能的作用机制进行了归纳。     

基于代谢分型的肿瘤生酮治疗敏感性及机制研究进展

能量代谢异常是肿瘤的基本特征之一。尽管靶向肿瘤代谢是一项公认的治疗策略,但临床治疗成功取决于准确的代谢分子分型。近期研究报道了肿瘤生酮治疗相关的两种代谢亚型:糖酵解型和酮体代谢型,两者表现为完全不同的代谢酶谱和线粒体功能状态,以及在体外和体内对生酮干预的不同反应。同时,在p53突变的肿瘤中,糖酵解亚型在葡萄糖限制的状态下可转变为酮体代谢型,随着酮体酶的表达激活及线粒体融合,出现生酮治疗抵抗。通过联用突变p53的变构激活剂,将突变的p53变成野生型的构象,可逆转酮体酶表达激活及线粒体代谢重编,保持稳定的酮体代谢缺陷表型。基于代谢亚型可以选择肿瘤生酮治疗的目标人群,通过基因突变状态可预测生酮治疗敏感性,从而建立精准肿瘤代谢调节治疗策略。     

Mediterranean dietary pattern and cancer risk in the EPIC cohort

Background:

Although several studies have investigated the association of the Mediterranean diet with overall mortality or risk of specific cancers, data on overall cancer risk are sparse.

Methods:

We examined the association between adherence to Mediterranean dietary pattern and overall cancer risk using data from the European Prospective Investigation Into Cancer and nutrition, a multi-centre prospective cohort study including 142 605 men and 335 873. Adherence to Mediterranean diet was examined using a score (range: 0–9) considering the combined intake of fruits and nuts, vegetables, legumes, cereals, lipids, fish, dairy products, meat products, and alcohol. Association with cancer incidence was assessed through Cox regression modelling, controlling for potential confounders.

Results:

In all, 9669 incident cancers in men and 21 062 in women were identified. A lower overall cancer risk was found among individuals with greater adherence to Mediterranean diet (hazard ratio=0.96, 95% CI 0.95–0.98) for a two-point increment of the Mediterranean diet score. The apparent inverse association was stronger for smoking-related cancers than for cancers not known to be related to tobacco (P (heterogeneity)=0.008). In all, 4.7% of cancers among men and 2.4% in women would be avoided in this population if study subjects had a greater adherence to Mediterranean dietary pattern.

Conclusion:

Greater adherence to a Mediterranean dietary pattern could reduce overall cancer risk.     

The relationship between diet and breast cancer in men (United States)

OBJECTIVES: The purpose of this paper was to investigate the relationship between food and beverage consumption and the development of breast cancer in men. METHODS: Possible relationships of dietary factors to risk of breast cancer in men were assessed in a case-control study conducted between 1983 and 1986. Cases (N = 220) were ascertained from ten population-based cancer registries. Controls (N = 291) were selected by random-digit dialing (< age 65) and from Health Care Financing Administration Medicare beneficiary lists (> or = age 65). RESULTS: No trends in risk were observed with increasing intakes of specific foods, except for an increase in risk with citrus fruits. No increase in risk with increasing amounts of specific fats, vitamins, or minerals or with amounts of protein, fiber, carbohydrate, starches, nitrites, or alcohol consumed was observed, except for an increase in risk with dietary vitamin C consumption. A decreasing trend in risk with dietary niacin and with coffee and an increasing trend in risk with tea consumption were observed. No associations were found with use of any dietary supplements, including vitamin C. CONCLUSIONS: The observed associations are not consistent with findings from studies of breast cancer in women and probably do not represent causal relationships. Dietary factors are unlikely to be strong determinants of breast cancer in men.     

Are the olive oil and other dietary lipids related to cancer? Experimental evidence

There is a wealth of evidence supporting the relationship between dietary lipids and cancer, particularly those of the breast, colon and rectum and prostate. The main support comes from the international correlational studies and, especially, from experimental ones. The evidence from human analytical studies is less consistent because of several conflicting findings, probably due to methodological issues. Experiemntally, it has been clearly demonstrated that quantity and type of dietary lipids as well as the particular critical phases of the carcinogenesis in which they act, are the essential factors in this relationship. Thus, whereas high dietary intake of n-6 polyunsaturated fatty acids (PUFA), primarily LA, and saturated fat has tumor-enhancing effects, long chain n-3 PUFA, CLA and GLA have inhibitory effects. Monounsaturated fatty acids (MUFA), mainly OA, present in high quantities in olive oil, seem to be protective although some inconsistent results have been reported. Bioactive compounds of virgin olive oil may also account for the protective effect of this oil, which is the main source of fat in the Mediterranean diet. Experimental studies have also provided evidence of several putative mechanisms of action of dietary lipids on cancer. Lipids can influence the hormonal status, modify cell membranes structure and function, cell signalling transduction pathways and gene expression, and modulate the function of the immune system. Although further studies are needed to evaluate and verify these mechanisms in humans, based on the multiple ways dietary lipids can act, they may have an important influence on tumorigenesis.     

Prospective study of dietary patterns and colorectal cancer among Singapore Chinese

An influence of Western diet and lifestyle factors observed among Singapore Chinese may contribute to the population's marked rise in colorectal cancer incidence over the past two decades. Thus far, however, there is little evidence for individual nutrients and foods as major contributing factors in this population. We evaluated whether patterns of food intake were associated with colorectal cancer in a population-based cohort of 61,321 Singapore Chinese that was established in 1993-98. Two dietary patterns, meat-dim sum and vegetable-fruit-soy, were previously identified by principal components analysis using baseline dietary data from a validated 165-item food frequency questionnaire. As of 31 December 2005, 961 incident colorectal cancer cases were diagnosed. Proportional hazards regression was used to calculate adjusted hazard ratios. Using nearly 10 years of follow-up data, we observed no association with either the meat-dim sum or vegetable-fruit-soy pattern for colorectal cancer. In conclusion, neither individual nutrients or foods nor dietary patterns appear to explain the rise in colorectal cancer among Singapore Chinese population.     

促炎性饮食与结直肠癌患病风险的Meta分析

目的 通过Meta分析评价促炎性饮食和结直肠癌患病风险的关系,为科学饮食提供参考依据。方法 截至2019年7月,系统检索英文数据库PubMed、Embase、Web of Science、Cochrane Library和中文数据库中国知网、万方数据库、维普数据库,筛选出饮食炎症效应与结直肠癌发病风险相关的文献。所纳入文献均采用膳食炎症指数（DII）来评价膳食的炎症效应。采用Revman 5.2软件进行Meta分析,对纳入研究的OR值及95%CI值进行合并,同时根据肿瘤类型和地域进行亚组分析。结果 共纳入文献10篇,参与者964 935例。Meta分析结果显示,最高促炎性饮食的个体与最高抗炎性饮食的个体相比较,结直肠癌的患病风险增加（OR=1.43,95％CI=1.28~1.60）。按肿瘤类型进行亚组分析显示,促炎性饮食的结肠癌患病风险增加（OR=1.37,95％CI=1.20~1.57）,直肠癌患病风险亦增加（OR=1.33,95％CI=1.11~1.61）。按地域进行亚组分析显示,促炎性饮食的结直肠癌的患病风险在亚洲（OR=2.17,95％CI=1.77~2.68）、欧洲（OR=1.56,95％CI=1.32~1.85）、北美（OR=1.28,95％CI=1.21 ~1.35）。结论 促炎性饮食可能会增加结直肠癌的患病风险。亚洲地区促炎性饮食与结直肠癌患病风险的相关性可能高于欧洲和北美洲,这一结论需要更多的研究进一步确认。