MOLECULAR REGULATION OF HUMAN MELANOMA METASTASIS

人类黑色素瘤转移的分子调控

• 批准号: 6172842
• 负责人: RAKESH K SINGH
• 金额: $ 10.16万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6172842
• 关键词: antisense nucleic acid; athymic mouse; autocrine; cell growth regulation; cell line; cytokine receptors; human tissue; immunocytochemistry; in situ hybridization; interleukin 8; melanoma; metastasis; molecular oncology; neoplasm /cancer classification /staging; receptor expression; transfection /expression vector

The major goal of our research is to define the mechanism(s) that regulate the process of metastasis, and use this knowledge to design innovative hypothesis-based therapies. Metastasis is a highly selective process that is regulated by multiple interrelated mechanisms whose outcome is dependent upon both the intrinsic properties of tumor cells and the host response. Signals from autocrine or paracrine pathways, alone or in combination, may regulate tumor growth and metastasis with the eventual outcome dependent on a balance of stimulatory and inhibitory factors. Recent data from our laboratory demonstrate that the organ microenvironment can modulate gene expression of growth and angiogenic factors in tumor cells in an organ site specific manner. Our analyses of different human metastatic melanoma cell variants demonstrated a direct correlation between the levels of interleukin-8 (IL-8) mRNA expression and protein secretion with metastatic phenotype in nude mice. Preliminary data from our laboratory and others suggest that IL-8 is an obligate autocrine growth, motility and angiogenic factor for melanoma cells. In this application we propose to test the hypothesis that autocrine production of IL-8 and its receptors and their regulation by organ specific cytokines are important determinant in melanoma growth and metastasis. Three specific aims will be pursued: First, we will determine the functional significance of the autocrine production of IL-8 and its receptors on the expression of cellular phenotypes associated with melanoma growth and metastasis. Second, we will analyze whether the organ microenivronments can differentially modulate the expression of IL-8 and its receptors in metastatic melanoma cells. Third, we will determine whether the expression of IL-8 correlates with the clinical grade of human melanoma tumor specimens. The knowledge gained from this research will extend our basic and clinical understanding of the mechanism(s) regulating the process of melanoma tumor growth and metastasis.

我们研究的主要目标是确定 调节转移的过程，并利用这些知识来设计 基于假设的创新疗法 转移是高度选择性的 这一过程由多个相互关联的机制调节， 结果取决于肿瘤细胞的内在特性 和宿主的反应。来自自分泌或旁分泌途径的信号， 单独或组合，可以调节肿瘤生长和转移， 最终的结果取决于刺激和 抑制因子 我们实验室的最新数据表明， 器官微环境可以调节生长的基因表达， 血管生成因子在肿瘤细胞中以器官部位特异性的方式。 我们 不同人转移性黑色素瘤细胞变体的分析 证明了白细胞介素-8水平与 （IL-8）mRNA表达和蛋白分泌与转移表型 在裸鼠中。 我们实验室和其他机构的初步数据表明 IL-8是一种专性自分泌生长、运动和血管生成因子 黑色素瘤细胞因子。 在本申请中，我们建议测试 IL-8及其受体自分泌产生假说 器官特异性细胞因子的调节是 黑色素瘤生长和转移。 将追求三个具体目标： 首先，我们将确定自分泌的功能意义， IL-8及其受体的产生对细胞表达的影响 与黑素瘤生长和转移相关的表型。 二是 将分析器官微环境是否能 调节转移性黑素瘤中IL-8及其受体的表达 细胞 第三，我们将确定IL-8的表达是否 与人黑素瘤肿瘤样本的临床等级相关。 从这项研究中获得的知识将扩展我们的基础和 临床了解调节过程的机制 黑色素瘤肿瘤生长和转移。