Regulation of metastasis by retinoic acid

视黄酸对转移的调节

• 批准号: 7188032
• 负责人: Eduardo F Farias
• 金额: $ 3.93万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7188032
• 关键词: Address; Adhesions; Agreement; All-Trans-Retinol; Apoptosis; Argentina; Binding; Binding Proteins; Biological; Biological Assay; Breast; Breast Cancer Model; Breast Carcinoma; CRBP I; Catabolism; Cell Line; Cell Proliferation; Cell model; Cell physiology; Cells; Cellular Structures; Cessation of life; Class; Collaborations; Collagen; Complementary DNA; Defect; Development; Dominant-Negative Mutation; Ductal Epithelial Cell; E-Cadherin; Embryonic Development; Endopeptidases; Enzymes; Epithelial; Epithelial Cells; Event; Gelatinase B; Genes; Genetic; Goals; Grant; Growth; Growth and Development function; High Pressure Liquid Chromatography; Homeostasis; Human; Individual; Injection of therapeutic agent; Institutes; Knockout Mice; Lung; Malignant - descriptor; Malignant Neoplasms; Mammary Tumorigenesis; Mammary gland; Matrix Metalloproteinases; Mediating; Messenger RNA; Metabolic; Methodology; Modeling; Molecular; Monitor; Mus; Mutant Strains Mice; Myoepithelial cell; Neoplasm Metastasis; Neoplastic Myoepithelial Cell; Numbers; Oncogenes; Organ; Peptide Hydrolases; Phase; Physiological; Plasminogen Activator Inhibitor 1; Predisposition; Process; Protein Isoforms; Proteins; Protocols documentation; Rate; Receptor Activation; Regulation; Reporter; Research; Retinoic Acid Receptor; Retinoids; Role; Signal Transduction; Simian virus 40; Source; System; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Tissue Inhibitor of Metalloproteinase-1; Transfection; Transgenic Mice; Transgenic Organisms; Tretinoin; Tumor Cell Invasion; Universities; Vimentin; Vitamin A; Western Blotting; base; carcinogenesis; cell behavior; cell growth; dimethylbenzanthracene; follow-up; genetically modified cells; immunocytochemistry; lymph nodes; malignant breast neoplasm; mammary epithelium; matrigel; medical schools; migration; monolayer; mutant; neoplastic cell; oncology; parent grant; receptor; research study; retinoic acid 4-hydroxylase; size; tumor; tumorigenesis

We propose to study the role of retinoic acid on events regulating tumor invasion and metastasis. This research will be done primarily in Argentina, at the Institute of Oncology "Anegel. H. Roffo", University of Buenos Aires, in collaboration with Rafael Mira-y-Lopez, Mount Sinai School of Medicine, as an extension of NCI grant CA-54273. Retinoic acid (RA), the chief bioactive metabolite of vitamin A, signals via RA receptors (RARs) and rexinoid receptors (RXR) to regulate diverse biological events essential for embryonic development and for organ homeostasis, cell growth, differentiation and death. Much evidence supports the notion that RA can interfere with oncogenesis, impairing tumor development and growth. However, the role of RA on the critical processes of tumor invasion and metastasis have not been systematically studied. Moreover, little is known about the role of myoepithelial cells, which interact closely with the ductal epithelial cells, on these key processes. Even less is known about the effects of RA on myoepithelial cells and its supporting role in transformation. A major goal of the parent grant is to define the role of physiological RA in mammary development and carcinogenesis but the parent grant does not address either invasion and metastasis or the role of myoepithelial cells. This collaborative proposal is meant to fill this gap. We will use a spontaneous murine mammary carcinoma model developed by the Foreign PI (LM38), which metastasizes to draining lymph nodes and lungs and contain both epithelial and myoepithelial cell components, and from which several sublines have been established. Our Specific Aims are to first characterize the ability of LM38 derivatives to biosynthesize RA and their expression of RARs and RXRs; second, to use receptor-selective retinoids to test the hypothesis that this class of agents modulate critical steps in the metastatic cascade (adhesion, migration, invasion, protease expression, etc); and third, to use genetically modified cells to specifically implicate distinct RAR and RXR species in the retinoid regulation of metastasis.

我们建议研究视黄酸在调节肿瘤侵袭和转移事件中的作用。这项研究将主要在阿根廷布宜诺斯艾利斯大学肿瘤学研究所“Anegel. H. Roffo”与西奈山医学院 Rafael Mira-y-Lopez 合作进行，作为 NCI 拨款 CA 的延伸-54273。视黄酸 (RA) 是维生素 A 的主要生物活性代谢物，通过 RA 受体 (RAR) 和类毒素受体 (RXR) 发出信号，调节胚胎发育和器官稳态、细胞生长、分化和死亡所必需的多种生物事件。许多证据支持 RA 可以干扰肿瘤发生、损害肿瘤发展和生长的观点。然而，RA在肿瘤侵袭和转移关键过程中的作用尚未得到系统研究。此外，人们对肌上皮细胞在这些关键过程中的作用知之甚少，肌上皮细胞与导管上皮细胞密切相互作用。关于 RA 对肌上皮细胞的影响及其在转化中的支持作用知之甚少。母基金的一个主要目标是确定生理性 RA 在乳腺发育和癌变中的作用，但母基金没有解决侵袭和转移或肌上皮细胞的作用。这项合作提案旨在填补这一空白。我们将使用国外PI（LM38）开发的自发性小鼠乳腺癌模型，该模型转移至引流管 淋巴结和肺，含有上皮细胞和肌上皮细胞成分，并从中建立了几个亚系。我们的具体目标是首先表征 LM38 衍生物生物合成 RA 的能力及其 RAR 和 RXR 的表达；其次，使用受体选择性视黄醇来检验此类药物调节转移级联中关键步骤（粘附、迁移、侵袭、蛋白酶表达等）的假设；第三，使用转基因细胞来明确不同的 RAR 和 RXR 物种在类维生素A调节转移中的作用。