MOLECULAR REGULATION OF HUMAN MELANOMA METASTASIS

我们研究的主要目的是明确(S) 调节转移的过程，并利用这一知识设计 创新的基于假设的疗法。转移是一种高度选择性的 由多个相互关联的机制调节的过程，其 结果取决于肿瘤细胞的内在属性 和宿主的反应。来自自分泌或旁分泌通路的信号， 单独或联合使用，可能通过以下途径调节肿瘤生长和转移 最终结果取决于刺激和刺激之间的平衡 抑制因素。我们实验室的最新数据表明， 器官微环境可以调节生长发育和基因表达。 肿瘤细胞中的血管生成因子以器官部位特异性的方式存在。我们的 不同人转移性黑色素瘤细胞变异体的分析 证实了白介素8水平与 (IL-8)基因表达和蛋白分泌与转移表型的关系 在裸鼠身上。来自我们实验室和其他人的初步数据表明 IL-8是一种专有的自分泌生长、运动和血管生成 黑色素瘤细胞的因子。在此应用程序中，我们建议测试 自分泌产生IL-8及其受体及其受体的假说 器官特异性细胞因子的调节是 黑色素瘤的生长和转移。我们会追求三个具体目标： 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 与黑色素瘤生长和转移相关的表型。第二，我们 将分析器官微环境是否能区分 IL-8及其受体在转移性黑色素瘤中的表达调控 细胞。第三，我们将确定IL-8的表达是否 与人黑色素瘤标本的临床分级相关。 从这项研究中获得的知识将扩展我们的基础和 S调节心绞痛过程机理的临床认识 黑色素瘤的生长和转移。

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.