DORMANCY VERSUS PROGRESSION OF HUMAN PRIMARY MELANOMA

描述：(改编自调查人员的摘要)大部分 原发皮肤黑色素瘤经历长时间的休眠生长 在获得恶性特征之前。与大多数其他原发肿瘤不同， 然而，这种休眠阶段在皮下/原位黑色素瘤中可见。 注射人黑色素瘤细胞系，从不同阶段获得 疾病的发展，变成裸鼠。因此，尽管几乎所有的高级 原代或转移性分化的阶段性细胞系逐渐发展为 生长缓慢的小斑块样病变--类似于放射状生长期 (RGP)或瘦垂直生长期(VGP)肿瘤。使用各种 方法，例如逆转录病毒插入突变或基因转染，这 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。这些细胞系呈现出一种 研究恶性前黑色素瘤基础的绝佳机会 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因素 控制原发黑色素瘤休眠的相互关联的因素。它们是： (I)对几种细胞因子介导的抑制性控制的敏感性， 包括IL-6；(Ii)黑色素瘤细胞在 多细胞生长环境；(3)诱导能力不足 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，基因改变思想 参与黑色素瘤的进展，例如p21WAF1或 P16INK4，通过同时影响几个或全部三个表型来实现这一点 (即细胞增殖、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对可能是世界上最 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，实验检查很少 模特们。它也可以作为影响因素的模型。 癌前-原发肿瘤休眠在其他类型的癌症中 早期的皮损材料严重有限，或者根本不存在。

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.