MOLECULAR REGULATION OF HUMAN MELANOMA METASTASIS

人类黑色素瘤转移的分子调控

• 批准号: 6513042
• 负责人: RAKESH K SINGH
• 金额: $ 10.4万
• 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 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6513042
• 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定义以下机制： 调节转移过程，并利用这些知识来设计 基于假设的创新疗法。 转移具有高度选择性 受多种相互关联的机制调节的过程 结果取决于肿瘤细胞的内在特性 以及主持人的回应。来自自分泌或旁分泌途径的信号， 单独或联合使用，可以调节肿瘤的生长和转移 最终结果取决于刺激和刺激的平衡 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和发育的基因表达 肿瘤细胞中的血管生成因子以器官位点特异性方式发挥作用。 我们的 不同人类转移性黑色素瘤细胞变体的分析 证明白细胞介素 8 水平之间存在直接相关性 (IL-8) mRNA 表达和蛋白质分泌与转移表型 在裸鼠中。 我们实验室和其他实验室的初步数据表明 IL-8 是一种专性自分泌生长、运动和血管生成的物质 黑色素瘤细胞的因子。 在此应用中，我们建议测试 假设 IL-8 及其受体的自分泌产生及其作用 器官特异性细胞因子的调节是重要的决定因素 黑色素瘤的生长和转移。 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可以差异化 调节转移性黑色素瘤中 IL-8 及其受体的表达 细胞。 第三，我们将确定IL-8是否表达 与人类黑色素瘤肿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 对调节过程的机制的临床理解 黑色素瘤肿瘤的生长和转移。

项目成果

Monocyte/macrophage recruitment, activation and differentiation modulate interleukin-8 production: a paracrine role of tumor-associated macrophages in tumor angiogenesis.

• 发表时间: 2002-11
• 期刊: In vivo
• 影响因子: 2.3
• 作者: M. Varney;Kimberlee J Olsen;R. Mosley;C. Bucana;J. Talmadge;Rakesh K. Singh

Regulation of constitutive and induced NF-kappaB activation in malignant melanoma cells by capsaicin modulates interleukin-8 production and cell proliferation.

辣椒素调节恶性黑色素瘤细胞中的组成型和诱导型 NF-κB 激活，从而调节 IL-8 的产生和细胞增殖。

• DOI: 10.1089/10799900252952217
• 发表时间: 2002
• 期刊: Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.
• 作者: Patel,PrabhudasS;Varney,MichelleL;Dave,BhavanaJ;Singh,RakeshK
• 通讯作者: Singh,RakeshK

IL-8 expression in malignant melanoma: implications in growth and metastasis.

恶性黑色素瘤中 IL-8 的表达：对生长和转移的影响。

• DOI: 10.14670/hh-15.843
• 发表时间: 2000
• 期刊: Histology and histopathology
• 影响因子: 2
• 作者: Singh,RK;Varney,ML
• 通讯作者: Varney,ML

Proteases as modulators of tumor-stromal interaction: primary tumors to bone metastases.

• DOI: 10.1016/j.bbcan.2007.11.001
• 发表时间: 2008-04
• 期刊: Biochimica et biophysica acta
• 作者: T. Wilson;Rakesh K. Singh

Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials.

• 发表时间: 2001-10
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Aihua Li;M. Varney;Rakesh K. Singh