Regulation of metastasis by retinoic acid

视黄酸对转移的调节

• 批准号: 7046170
• 负责人: Eduardo F Farias
• 金额: $ 4.05万
• 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/7046170
• 关键词: apoptosis; biological signal transduction; breast neoplasms; hormone therapy; immunocytochemistry; laboratory mouse; mammary epithelium; metastasis; microarray technology; neoplasm /cancer chemotherapy; nuclear receptors; nutrition related tag; retinoate; retinoid binding proteins; terminal nick end labeling; western blottings

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的事件中的作用。这项研究将主要在布宜诺斯艾利斯大学的肿瘤学研究所“Anegel。H.Roffo”研究所与NCI Grant CA-54273的延伸，作为NCI Grant CA-54273。视黄酸（RA），维生素A的主要生物活性代谢产物，通过RA受体（RARS）和雷克内斯受体（RXR）的信号调节对胚胎发育以及器官稳态，细胞生长，分化和死亡必不可少的生物学事件的多种生物学事件。许多证据支持RA可以干扰肿瘤发生，损害肿瘤发育和生长的观念。但是，RA在肿瘤侵袭和转移的关键过程中的作用尚未系统地研究。此外，对与导管上皮细胞紧密相互作用在这些关键过程中紧密相互作用的肌上皮细胞的作用知之甚少。关于RA对肌上皮细胞的影响及其在转化中的支持作用的知之甚少。父母赠款的一个主要目标是定义生理RA在乳腺发育和致癌作用中的作用，但父授予没有解决侵袭和转移或肌上皮细胞的作用。该协作提案旨在填补这一空白。我们将使用外国PI（LM38）开发的自发鼠乳腺癌模型，该模型转移到排水 淋巴结和肺部均包含上皮和肌上皮细胞成分，并从中建立了几种subline。我们的具体目的是首先表征LM38衍生物对生物合成RA的能力及其对RAR和RXR的表达的能力。第二，使用受体选择性类维生素类动物测试以下假设：该类别的药物调节转移性级联反应的关键步骤（粘附，迁移，侵袭，蛋白酶表达等）；第三，使用遗传修饰的细胞特异性地暗示了在转移的类维生素类动物调节中的不同RAR和RXR物种。