DORMANCY VERSUS PROGRESSION OF HUMAN PRIMARY MELANOMA

人类原发性黑色素瘤的休眠与进展

• 批准号: 6489064
• 负责人: ROBERT S KERBEL
• 金额: $ 16.58万
• 依托单位: SUNNYBROOK & WOMEN'S COLL HLTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-06-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6489064
• 关键词: angiogenesis; athymic mouse; cell growth regulation; cytokine; genetic regulation; host neoplasm interaction; interleukin 6; melanoma; molecular oncology; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplastic growth; neoplastic process; oncoprotein p21; tissue /cell culture; transfection; transposon /insertion element; vascular endothelial growth factors

DESCRIPTION: (adapted from the investigator's abstract) The majority of primary cutaneous melanomas go through a prolonged period of dormant growth before acquiring malignant properties. Unlike most other primary tumors, however, this dormancy stage is visible in melanomas, subdermal/orthotopic injection of human melanoma cell lines, obtained from different stages of disease progression, into nude mice. Thus, whereas almost all advanced stage primary or metastatic-derived cell lines give rise to progressively small slow-growing, plaque-like lesions -- similar to radial growth phase (RGP) or thin vertical growth phase (VGP) tumors in humans. Using various methods, e.g. retroviral insertional mutagenesis or gene transfection, this applicant has recently succeeded in isolating tumorigenic variants from a number of such early-stage primary melanomas. These cell lines present an outstanding opportunity to study the basis of pre-malignant melanoma dormancy and the reasons for its termination. First, (based on their recent results), they believe there are three major interconnected factors which govern primary melanoma dormancy. These are: (i) sensitivity to inhibitory controls mediated by several cytokines, including IL-6; (ii) a deficient capacity of melanoma cells to survive in a multicellular growth context; (iii) a deficient ability to induce angiogenesis; Second, overcoming these 'defects' results in acquisition of overt malignant growth characteristics. Third, genetic alterations thought to be involved in the progression of melanomas, such as loss of p21WAF1 or p16INK4, do so by affecting several, or all three phenotypes simultaneously (i.e., cell proliferation, survival, and angiogenesis). Examination of these hypotheses comprise the three specific aims of the research program. The proposed research will shed new light on what is probably the most crucial stage of melanoma progression, but which, thus far, has received little experimental scrutiny because of the lack of appropriate experimental models. It may also serve as a model for factors influencing premalignant-primary tumor dormancy in other types of cancer where access to early-stage lesional material is severely limited, or non-existent.

描述：（改编自研究者摘要）大多数 原发性皮肤黑色素瘤经过长时间的休眠生长 在获得恶性特性之前。 与大多数其他原发性肿瘤不同， 然而，这种休眠阶段在黑色素瘤中是可见，皮下/原位 注射人黑色素瘤细胞系，从不同阶段的 疾病进展，进入裸鼠。 几乎所有先进的， 阶段性原代或转移来源细胞系逐渐产生 小的缓慢生长的斑块样病变-类似于放射状生长期 (RGP)或人的薄垂直生长期（VGP）肿瘤。 使用各种 方法，例如逆转录病毒插入诱变或基因转染， 申请人最近成功地从一种 这种早期原发性黑色素瘤的数量。 这些细胞系呈现出 研究恶性黑色素瘤前病变基础的绝佳机会 休眠及其终止的原因。 首先，（根据他们最近的结果），他们认为有三个主要的 控制原发性黑色素瘤休眠的相互关联的因素。 这些是： (i)对由几种细胞因子介导的抑制控制的敏感性， 包括IL-6;（ii）黑色素瘤细胞在肿瘤细胞中存活的能力不足， 多细胞生长环境;（iii）诱导 血管生成;第二，克服这些“缺陷”导致获得 明显的恶性生长特征。 第三，基因改造思想 参与黑色素瘤的进展，如p21 WAF 1或 p16 INK 4通过同时影响几种或所有三种表型来实现 (i.e.,细胞增殖、存活和血管生成）。 审查 这些假设构成了研究计划的三个具体目标。 这项拟议中的研究将揭示什么可能是最重要的 黑色素瘤进展的关键阶段，但到目前为止， 由于缺乏适当的实验， 模型 它也可以作为影响因素的模型 在其他类型的癌症中， 早期损伤物质严重受限或不存在。