TUMOR HOST INTERACTIONS IN HUMAN MELANOMA METASTASIS

背景：对负增长损失的性质知之甚少 控制在人类皮肤黑色素瘤的背景下，以及这种损失是如何 可能会影响疾病的发展和恶性进展。在……里面 在当前赠款期间进行的研究获得了证据 关于负增长控制的三个新的重要方面 (及其颠覆性)在人类黑色素瘤中。它们是：(I)成纤维细胞或 内皮细胞来源(即旁分泌)白介素6(IL-6)可在 体外作为一种有效的黑色素瘤细胞株的生长抑制物 早期可治愈的原发病变，而来自更多 晚期转移能力强的皮损对此有抵抗力。 抑制作用；(Ii)在晚期的一个重要亚组(50%-70%) 黑色素瘤细胞株IL-6似乎被激活并发挥作用 体外有丝分裂自分泌生长因子--我们称之为 “细胞因子转换”；(3)一些其他细胞因子(IL-1、转化生长因子-β、 肿瘤坏死因子-α和抑癌素M)也可以在体外发挥生长作用 早期黑色素瘤的抑制剂，而这种作用减弱或 完全丧失了肿瘤进展--我们称之为 “多核细胞耐药”。 问题：上述所有结果都是在体外获得的 使用已建立的黑色素瘤细胞系。的下一个逻辑阶段 研究是为了研究这些在体外的意义。 人体实验和临床活体行为的研究结果 黑色素瘤及其相关的分子机制。 总体指导假设和具体目标：假设IL-6 耐药本身、一般多细胞因子耐药和IL-6“细胞因子” 转换“有助于人类黑色素瘤的恶性侵袭性。 具体目标是：(1)评估旁分泌和/或旁分泌的能力 自分泌IL-6以改变体内人类黑色素瘤的生长(即在 裸鼠)，并最终作为生长刺激剂；(Ii)评估 人黑色素瘤组织中IL-6mRNA和蛋白的相对表达 样本(在疾病的不同阶段)，并作为可能的预后 黑色素瘤侵袭性的指标；(Iii)确定分子 IL-6信号转导改变的特点 黑色素瘤细胞对IL-6的耐药性。 意义：拟议的实验与以下方面有关： 几个问题包括：(I)帮助揭示 人类皮肤黑色素瘤的进展和发病机制，(Ii) 阐明“造血型”细胞因子的作用及负性缺失 黑色素瘤病理生物学的生长控制。尽管我们的实验表明 它们可能只与人类黑色素瘤有更广泛的相关性，因为它是 现在已知多种人类癌症都会产生IL-6， 它的临床意义在很大程度上是未知的。

Background: Little is known about the nature of loss of negative growth controls in the context of human cutaneous melanoma, and how such losses may affect the development and malignant progression of the disease. In studies undertaken during the current grant period evidence was obtained for what may be three new important aspects of negative growth control (and its subversion) in human melanoma. These are: (i) fibroblast or endothelial derived (ie. paracrine) interleukin-6 (IL-6) can function in vitro as a potent growth inhibitor of melanoma cell lines established from early-stage curable primary lesions, whereas cell lines from more advanced, metastatically-competent, lesions are resistant to this inhibitory effect; (ii) in a significant subset (50-70%) of advanced-stage melanoma cell lines, IL-6 appears to be switched on and function as a mitogenic autocrine growth factor in vitro - a process we have termed "cytokine switching"; (iii) a number of other cytokines (IL-1, TGF-beta, TNF-alpha and oncostatin M) can also function in vitro as growth inhibitors for early-stage melanomas, whereas this effect is diminished or lost altogether with tumor progression - a phenomenon we have termed "multicytokine resistance". The Problem: All of the aforementioned results were obtained in vitro using established melanoma cell lines. The next logical phases of investigation are to investigate the significance of these in vitro findings to the experimental and clinical in vivo behavior of human melanomas, and the molecular mechanisms involved. Overall Guiding Hypothesis and Specific Aims: It is hypothesized that IL-6 resistance per se, multicytokine resistance in general, and IL-6 "cytokine switching" contribute to the malignant aggressiveness of human melanoma. The specific aims are: (i) to evaluate she capacity of paracrine and/or autocrine IL-6 to alter the growth of human melanomas in vivo (i.e. in nude mice), and ultimately to act as a growth stimulant; (ii) to evaluate the relative expression of IL-6 mRNA and protein in human melanoma tissue samples (at different stages of disease), and as possible prognostic indicators of melanoma aggressiveness; (iii) to determine the molecular characteristics of IL-6 signal transduction alterations responsible for IL-6 resistance in melanoma cells. Significance: The proposed experiments are significant in relation to several issues including: (i) helping to uncover part of the basis for the progression and pathogenesis of human cutaneous melanomas and, (ii) elucidating the role of "hemopoietic" cytokines and (loss of) negative growth controls in melanoma pathobiology. Although our experiments deal only with human melanoma they may have much broader relevance since it is now known that a diverse array of human carcinomas produce IL-6, the clinical significance of which is largely unknown.