Short chain fatty acid metabolism and colonic tumorigenesis

短链脂肪酸代谢与结肠肿瘤发生

基本信息

批准号：
7305988
负责人：
Barbara Heerdt
金额：
$ 13.94万
依托单位：
MONTEFIORE MEDICAL CENTER (BRONX, NY)
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-09 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7305988
关键词：
Acyl CoA Dehydrogenases Alleles Apoptosis Appendix Bacteria Butyrates Carcinoma Cell Cycle Arrest Cell Line Cell Lineage Cell Maturation Cell division Cells Chemical Models Chemoprotective Agent Clinical Research Colon Colon Carcinoma Colon, Rectum Colonic Neoplasms Colorectal Cancer Complement Data Development Dietary Factors Dietary Fiber Disease Elevation Energy-Generating Resources Epithelial Cells Evaluation Exposure to Failure Fatty Acids Fermentation Fiber Genes Genetic Genetic Models Genus Cola Goals Goblet Cells Growth Histone Deacetylase Histopathology Homeostasis Human In Vitro Individual Inherited Intervention Studies Intestinal Mucosa Intestinal Neoplasms Intestines Invasive Large Intestine Lead Life Link Malignant Epithelial Cell Malignant Neoplasms Mediating Membrane Potentials Metabolic Metabolism Metastatic Lesion Metastatic to Mitochondria Modeling Mucins Mus Mutation N-3 polyunsaturated fatty acid Other Genetics Pathway interactions Phenotype Physiological Population Positioning Attribute Prevention strategy Preventive Process Publishing Rectal Cancer Rectal Tumors Rectum Regulation Relative Risks Reporting Risk Role Site Small Intestines Time Tissues Transgenes Tumor Suppression Volatile Fatty Acids Work adenoma base butyrate cancer cell chemical carcinogen chemical genetics fatty acid metabolism in vivo mitochondrial membrane mouse model novel oxidation rectal research study response tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Short chain fatty acids (SCFAs), such as butyrate (NaB), are derived from fermentation of dietary fiber and present at very high levels in the colon. In vitro, SCFAs induce colonic carcinoma cell maturation (cell cycle arrest, lineage specific differentiation and apoptosis) at concentrations that are at least an order of magnitude lower than those found in the colonic lumen. Therefore, whereas it is likely that SCFAs naturally suppress development and/or progression of colon cancer by mediating colonic epithelial cell maturation, this suppression can clearly fail since colon cancer is a prevalent disease. Our extensive prior work has demonstrated that, besides butyrate's HDAC inhibiting activity, its mitochondrial ¿-oxidation by colonic epithelial cells is necessary for its complete induction of colonic carcinoma cell maturation in vitro. We showed this is also true in vivo by using a mouse with a homozygous genetic inactivation of short chain acyl dehydrogenase (Scad), which encodes the first step in ¿-oxidation of SCFAs. In Scad-/- mice, apoptosis was suppressed greater than 90% in the proximal colon, but not in the small intestine, consistent with the fact that colonic cells are normally exposed to high levels of SCFAs and have integrated their metabolism into regulation of tissue homeostasis. In contrast, small intestinal cells, not normally exposed to these higher levels of SCFAs, do not utilize these compounds in the same way. Recently, we and our collaborators have established novel mouse genetic models that initiate colon cancer in the large intestine, rather than in the small intestine - the site of tumor formation consistently found in mice that inherit a constitutive mutation of the Apc gene. Consequently, we are now in a unique position to use a genetic approach to prove that SCFAs suppress tumor formation in the colon, the site at which they induce cell maturation in vivo. Both an Apcflox/+ mouse, in which the floxed Apc allele is excised by a CDX2:cre transgene targeted to the colon, and the Muc2-/- mouse, develop colon tumors. The Scad-/- mutation will be introduced into each of these models to abrogate SCFA metabolism in order to determine how this alters homeostasis of the intestinal mucosa and tumor development. Moreover, we have demonstrated that the mitochondrial membrane potential (??m) is fundamental in regulating colonic cell maturation pathways, and recently reported that stable elevations in the ??m are linked to reduced response of cells to NaB, but enhanced invasive and metastatic phenotypes in vitro. Therefore, we hypothesize that abrogation of the ability of colonic epithelial cells to undergo maturation pathways in vivo, by introduction of the Scad-/- mutation into the Apcflox/+ and Muc2-/- models, will lead to more aggressive tumors and progression to the metastatic phenotype, the latter not yet achieved for genetically initiated colon cancer.

描述（由申请人提供）：短链脂肪酸（SCFA），例如丁酸盐（NaB），源自膳食纤维的发酵，并且在结肠中以非常高的水平存在。在体外，SCFA诱导结肠癌细胞成熟（细胞）。周期停滞、谱系特异性分化和细胞凋亡）的浓度至少比结肠腔中发现的浓度低一个数量级，因此，SCFA 很可能自然抑制结肠癌的发生和/或进展。通过介导结肠上皮细胞成熟，这种抑制显然会失败，因为结肠癌是一种普遍的疾病，我们之前的大量工作已经证明，除了丁酸盐的 HDAC 抑制活性之外，它的线粒体 ¿ -结肠上皮细胞的氧化对于其在体外完全诱导结肠癌细胞成熟是必要的。我们通过使用编码第一个短链酰基脱氢酶（Scad）的纯合基因失活的小鼠证明了这在体内也是如此。介入 ¿ - SCFA 的氧化作用在 Scad-/- 小鼠中，近端结肠中的细胞凋亡被抑制超过 90%，但在小肠中则不然，这与结肠细胞通常暴露于高水平的 SCFA 并整合其自身的事实一致。相比之下，通常不接触这些较高水平的 SCFA 的小肠细胞不会以相同的方式利用这些化合物。最近，我们和我们的合作者建立了新型小鼠遗传模型，可以启动结肠癌症发生在大肠，而不是小肠——肿瘤形成的部位在遗传了 Apc 基因组成型突变的小鼠中一致发现，我们正在测试。现在处于独特的地位，可以使用遗传方法来证明 SCFA 可以抑制肿瘤的形成结肠，这是它们在体内诱导细胞成熟的部位。 floxed Apc 等位基因被靶向结肠的 CDX2:cre 转基因切除，而 Muc2-/- 小鼠， Scad-/-突变将被引入到这些模型中以消除结肠肿瘤。 SCFA 代谢以确定其如何改变肠粘膜的稳态此外，我们已经证明线粒体膜电位。 (??m) 对于调节结肠细胞成熟途径至关重要，最近报道称 ??m 的稳定升高与细胞对 NaB 的反应减弱有关，但侵袭性增强因此，我们认为这种能力被废除了。通过引入 Scad-/- 突变，结肠上皮细胞在体内经历成熟途径进入 Apcflox/+ 和 Muc2-/- 模型，将导致更具侵袭性的肿瘤并进展至转移表型，后者尚未在基因引发的结肠癌中实现。