Vitamin D3 and Intestinal Tumorigenesis

维生素 D3 与肠道肿瘤发生

• 批准号: 7994143
• 负责人: LEONARD H AUGENLICHT
• 金额: $ 14.73万
• 依托单位: MONTEFIORE MEDICAL CENTER (BRONX, NY)
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994143
• 关键词: Aberrant crypt foci; Affect; Animals; Apoptosis; Blood Circulation; Cell Line; Cell Nucleus; Cells; Chemopreventive Agent; Chemoprotective Agent; Cholecalciferol; Coculture Techniques; Colon; Colon Carcinoma; Colonic Neoplasms; Cytoplasm; Data; Development; Diet; Disease; Epithelial Cells; Event; Genetic Models; Growth; Homeostasis; Human; In Vitro; Institution; Intake; Intestinal Neoplasms; Intestines; Invaded; Investigation; Link; Macrophage Activation; Malignant Neoplasms; Molecular Target; Mus; Neoplasm Metastasis; Pathway interactions; Peripheral; Phosphorylation; Preneoplastic Change; Prevention; Publishing; Rattus; Risk; Serum; Signal Transduction; Stream; Testing; Transgenes; Vitamin D; Vitamin D3 Receptor; Work; cancer cell; cell growth; cell type; cytokine; high risk; in vivo; macrophage; mouse model; neoplastic cell; novel; public health relevance; receptor; response; tumor; tumor progression; tumorigenesis; villin

DESCRIPTION (provided by applicant): Vitamin D3 intake and serum levels are key determinants in establishing risk for human colon cancer, and vitamin D3 has been shown to inhibit the development of AOM induced aberrant crypt foci, and tumors in ApcMin mice. Most studies of mechanism have focused on colon epithelial cell lines in culture, documenting significant effects on proliferation and/or apoptosis, and pathways associated with these cellular responses. However, we recently discovered that in vitro, vitamin D3 disrupts, in a vitamin D receptor-dependent manner, the ability of macrophages to stimulate colon tumor cell growth, and have dissected a specific mechanism and cascade of signaling events disrupted by vitamin D3 in the macrophages by which they signal to the epithelial cells. We will use a novel VDRflox/flox mouse, in which we will target inactivation of the vitamin D receptor to macrophages/monocytic or epithelial cells by introduction of a cfms-cre or villin-cre transgene, respectively. By introducing these constructs into the Apc1638N/+ mouse, we will determine the contribution of the different cell compartments to the effects of vitamin D3 on intestinal homeostasis and prevention of preneoplastic changes and tumor development, and will determine the effects of vitamin D3 in these mice on the specific cross-talk between pathways we have discovered. Establishment that vitamin D3 targets macrophages, as well as epithelial cells, in vivo, and aborts the signals they send to stimulate tumor epithelial cell growth, will establish a new paradigm regarding how vitamin D3 is chemopreventive for colon cancer. PUBLIC HEALTH RELEVANCE: Low levels of vitamin D3 in humans are linked to higher risk for colon (and other) cancers, and elevating vitamin D3 has been shown to be chemoprotective for intestinal tumor development in humans, and in rat and mouse models of the disease. Most studies of how vitamin D influences tumor development have focused on how it affects the growth of epithelial cells of the tumor, the actual malignant cell that invades and metastasizes. However, tumors are made up of many different cell types, and we have recently discovered that other cells in the tumor (macrophages/monocytic cells) can send specific signals to the epithelial cells to cause them to grow more rapidly, and have dissected just which molecules are involved both in the macrophages and the epithelial cells in the "cross-talk". Strikingly, vitamin D3 can inhibit the ability of the macrophages to make and send these signals, thus indicating that macrophages may be a key target in how vitamin D3 inhibits the development and progression of cancer. We have novel mice which have been genetically manipulated so that only the epithelial cells or the macrophages/monocytic cells can respond to vitamin D3. We will use these to prove that macrophages are also key targets in vitamin D3 inhibition of intestinal tumors, and will also determine whether the molecular targets in these animals are the same as those we have discovered when macrophages and epithelial cells are co-cultured together as purified cells.

描述(由申请人提供)： 维生素D3摄入量和血清水平是确定人类结肠癌风险的关键决定因素，维生素D3已被证明可以抑制AOM诱导的异常隐窝病灶和ApcMin小鼠肿瘤的发展。大多数机制的研究都集中在培养的结肠上皮细胞系上，记录了对增殖和/或凋亡的显著影响，以及与这些细胞反应相关的途径。然而，我们最近发现，在体外，维生素D3以维生素D受体依赖的方式干扰巨噬细胞刺激结肠癌细胞生长的能力，并剖析了维生素D3破坏巨噬细胞向上皮细胞发出信号的特定机制和一系列信号事件。我们将使用一种新型的VDRFLOX/FLOX小鼠，在该小鼠中，我们将分别通过引入cfms-cre或Villin-cre转基因来针对巨噬细胞/单核细胞或上皮细胞的维生素D受体失活。通过将这些结构引入Apc1638N/+小鼠，我们将确定不同的细胞室在维生素D3对肠道内稳态以及预防癌前病变和肿瘤发展的影响中的作用，并将确定这些小鼠中维生素D3对我们已发现的通路之间的特定串扰的影响。确定维生素D3在体内以巨噬细胞和上皮细胞为靶点，并终止它们发出的刺激肿瘤上皮细胞生长的信号，将建立关于维生素D3如何化学预防结肠癌的新范式。 公共卫生相关性： 人类体内维生素D3水平低与患结肠癌(和其他)癌症的风险较高有关，而提高维生素D3水平已被证明对人类以及这种疾病的大鼠和小鼠模型的肠道肿瘤的发展具有化学保护作用。大多数关于维生素D如何影响肿瘤发展的研究都集中在它如何影响肿瘤上皮细胞的生长，肿瘤上皮细胞是真正的侵袭和转移的恶性细胞。然而，肿瘤是由许多不同的细胞类型组成的，我们最近发现，肿瘤中的其他细胞(巨噬细胞/单核细胞)可以向上皮细胞发送特定的信号，使它们更快地生长，并在“串扰”中剖析了哪些分子参与了巨噬细胞和上皮细胞的生长。值得注意的是，维生素D3可以抑制巨噬细胞制造和发送这些信号的能力，从而表明巨噬细胞可能是维生素D3如何抑制癌症发展和进展的关键靶点。我们有了新的小鼠，这些小鼠经过了基因操作，只有上皮细胞或巨噬细胞/单核细胞对维生素D3有反应。我们将利用这些来证明巨噬细胞也是维生素D3抑制肠道肿瘤的关键靶点，并将确定这些动物的分子靶点是否与我们在巨噬细胞和上皮细胞作为纯化细胞共同培养时发现的相同。