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Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention

World Journal of Gastrointestinal Oncology 2014年第2期6卷 41-51页

作者： Huawei Zeng Darina L Lazarova michael bordonaro United States Department of Agriculture Agricul-tural Research ServiceGrand Forks Human Nutrition Research Center Department of Basic Sciences The Commonwealth Medical College

Many epidemiological and experimental studies have suggested that dietary fiber plays an important role in colon cancer prevention. These findings may relate to the ability of fiber to reduce the contact time of carcinogens within the intestinal lumen and to promote healthy gut microbiota, which modifies the host's metabolism in various ways. Elucidation of the mechanisms by which dietary fiber-dependent changes in gut microbiota enhance bile acid deconjugation, produce short chain fatty acids, and modulate inflammatory bioactive substances can lead to a better understanding of the beneficial role of dietary fiber. This article reviews the current knowledge concerning the mechanisms via which dietary fiber protects against colon cancer.

关键词： Dietary fiber Gut microbiota Colon cancer

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Approaches that ascertain the role of dietary compounds in colonic cancer cells

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World Journal of Gastrointestinal Oncology 2014年第1期6卷 1-10页

作者： michael bordonaro Koen Venema Adeline K Putri Darina Lazarova Department of Basic Sciences The Commonwealth Medical College TNO Research group Kinetics Research for Food and Pharma Maastricht University Health Food Innovation ManagementCampus Venlo

Preventive approaches against cancer have not been fully developed and *** example,the incidence of some types of cancer,including colon cancer,is highly dependent upon lifestyle,and therefore,amenable to *** the lifestyle factors,diet strongly affects the incidence of colon cancer; however,there are no definitive dietary recommendations that protect against this *** association between diet-derived bioactives and development of colonic neoplasms will remain ill defined if we do not take into account:(1) the identity of the metabolites present in the colonic lumen;(2) their concentrations in the colon; and(3) the effect of the colonic contents on the function of individual *** review two approaches that address these questions:the use of fecal water and in vitro models of the human *** to treatment with individual diet-derived compounds,the exposure of colon cancer cells to samples from fecal water or human colon simulators mimics closer the in vitro conditions and allows for more reliable studies on the effects of diet on colon cancer *** rationale and the advantages of these strategies are discussed from the perspective of a specific question on how to analyze the combined effect of two types of bioactives,butyrate and polyphenol metabolites,on colon cancer cells.

关键词： Human colon model Fecal water Diet Colon cancer Prevention Butyrate Polyphenols WNT signaling

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CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer

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World Journal of Gastroenterology 2015年第27期21卷 8238-8248页

作者： michael bordonaro Darina L Lazarova Department of Basic Sciences The Commonwealth Medical College Scranton

This paper reviews the distinctive roles played by the transcriptional coactivators CREB-binding protein(CBP) and p300 in Wnt/β-catenin signaling and cell physiology in colorectal cancer(CRC). Specifically, we focus on the effects of CBP- and p300-mediated Wnt activity on(1) neoplastic progression;(2) the activities of butyrate, a breakdown product of dietary fiber, on cell signaling and colonic cell physiology;(3) the development of resistance to histone deacetylase inhibitors(HDACis), including butyrate and synthetic HDACis, in colonic cells; and(4) the physiology and number of cancer stem cells. Mutations of the Wnt/β-catenin signaling pathway initiate the majority of CRC cases, and we have shown that hyperactivation of this pathway by butyrate and other HDACis promotes CRC cell apoptosis. This activity by butyrate may in part explain the preventive action of fiber against CRC. However, individuals with a high-fiber diet may still develop neoplasia; therefore, resistance to the chemopreventive action of butyrate likely contributes to CRC. CBP or p300 may modify the ability of butyrate to influence colonic cell physiology since the two transcriptional coactivators affect Wnt signaling, and likely, its hyperactivation by butyrate. Also, CBP and p300 likely affect colonic tumorigenesis, as well as stem cell pluripotency. Improvement of CRC prevention and therapy requires a better understanding of the alterations in Wnt signaling and gene expression that underlie neoplastic progression, stem cell fate, and the development of resistance to butyrate and clinically relevant HDACis. Detailed knowledge of how CBP- and p300 modulate colonic cell physiology may lead to new approaches for anti-CRC prevention and therapeutics, particularly with respect to combinatorial therapy of CBP/p300 inhibitors with HDACis.

关键词： CREB-binding protein p300 Wnt colorectalcancer butyrate stem cells

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膳食纤维、肿瘤干细胞和Wnt信号活性的连续谱:结肠直肠癌预防和治疗的可能性

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癌症 2008年第7期27卷 766-770页

作者： michael bordonaro Alan C. Sartorelli Department of Pharmacology and Developmental Therapeutics Program Cancer CenterYale University School of MedicineNew HavenCT 06520USA

Wnt信号转导参与了人类结肠直肠癌(colorectal cancer,CRC)的发生。尽管Wnt信号转导活性与细胞增殖间的关系已经明了,但也有研究表明,高水平的Wnt活性与细胞凋亡间存在关系。我们分析了10种人类CRC细胞系,结果发现组蛋白去乙酰酶抑制剂(... 详细信息

Wnt信号转导参与了人类结肠直肠癌(colorectal cancer,CRC)的发生。尽管Wnt信号转导活性与细胞增殖间的关系已经明了,但也有研究表明,高水平的Wnt活性与细胞凋亡间存在关系。我们分析了10种人类CRC细胞系,结果发现组蛋白去乙酰酶抑制剂(inhibitors of histone deacetylases,HDACis),例如丁酸盐,可通过过度诱导Wnt信号转导而促使CRC细胞凋亡;因此,通过HDACis过度活化Wnt信号转导可作为结肠直肠癌新的预防和治疗措施。我们的研究结果可以解释膳食纤维及其产物丁酸盐对于CRC保护作用的研究结果和丁酸盐的抗肿瘤作用为何相互矛盾。我们认为,体外研究中观察到的Wnt活性水平和CRC细胞凋亡水平的变化表明体内存在CRC细胞亚型,它们对于丁酸盐的反应程度不同。Wnt活性与肠道干细胞的更新和CRC干细胞的转移潜能相关,本文在此基础上讨论HDACis介导的Wnt信号转导调节作为CRC干细胞治疗方法的可能性,认为对Wnt阳性的CRC干细胞进行靶向治疗可作为CRC的基因疗法。

关键词：肿瘤干细胞膳食纤维结肠直肠肿瘤 Wnt 丁酸盐凋亡 β-catenin 组蛋白去乙酰酶抑制剂

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