TUMOR PROGRESSION AND THE IMMUNOBIOLOGY OF METASTASIS

这项建议可以分为三个部分。第一，是 直接扩展了我们之前关于基因组不稳定性的工作 肿瘤进展。我们测量了自发性的比率 转移性肿瘤的突变和核型改变的发生 和非转移性细胞，但不能证明在 单元格类型之间的任一参数。然而，因为 我们选择的参数可能是有限的(点突变)或 对于广义(细胞遗传学变化)，我们选择了观察 同源重排(HR)作为一种确定是否 转移性与非转移性心率差异有统计学意义 可以检测到细胞。 这项提案的第二部分扩大了我们对 克隆显性问题的研究进展 进展的，即转移的细胞的发育。最近的报道 已经表明(在小鼠模型中)当肿瘤发生转移时 一个克隆人不仅控制着原发肿瘤，而且还控制着 转移瘤。我们将使用分子技术来解决这个问题 并确定克隆优势是否是一种特征 人类肿瘤的症状。因为我们相信克隆的机制 显性的发生与基因组的不稳定有关(请参阅正文)， 这些分析建立了基因组之间的合理联系 不稳定和进步。这个问题也将在中进行分析 乳头状瘤癌变过程中的致癌模型 癌症。 该提案的第三部分涉及我们的假设 肿瘤进展有两种类型，即所见的经典形式。 在结肠癌(类型1)和加速形式(类型2)中， 这在大多数其他肿瘤中都会发生。我们选择了未知的初选 肿瘤是2型肿瘤的典型例子 进步者。这些研究的目的是定义II型肿瘤 使用核型分析来努力定义独特的染色体 这些肿瘤的变化。我们还计划使用这些方法 包含在前两个部分中，以研究 类型1和类型2之间的进步者。 因此，我们提议继续我们先前的工作。 并利用分子遗传技术将其扩展到更新的领域 以评估基因组不稳定性和肿瘤进展。

This proposal can be divided into three sections. The first, is direct extension of our previous work on genomic instability in tumor progression. We had measured the rate of spontaneous mutation and of the generation of karyotypic changes in metastatic and non-metastatic cells but could not demonstrate a difference in either parameter between the cell types. However, because the parameters we chose may have been to finite (point mutations) or to broad (cytogenetic changes), we have chosen to look at homologous rearrangements (HR) as a means of determining if significant differences in HR for metastatic and non-metastatic cells can be detected. The second section of this proposal extends our interest in progression to the issue of clonal dominance in relationship to the development of progressed, i.e. metastatic cells. Recent reports have indicated (in a murine model) that as tumors become metastatic a single clone dominates not only the primary tumor, but also the metastases. We will use molecular techniques to address this issue in human tumors and determine whether clonal dominance is a feature of human neoplasia. Since we believe the mechanism by which clonal dominance occurs relates to genomic instability (please see text), these analyses establish a reasonable link between genomic instability and progression. This issue will also be analyzed in a carcinogenesis model during the conversion of papillomas to carcinomas. The third section of this proposal deals with our hypothesis that tumor progression is of two types, namely the classic form as seen in colon carcinoma (Type 1) and the accelerated form, (Type 2), which occurs in most other tumors. We have chosen unknown primary tumors as being the quintessential example of a Type 2 tumor progressor. These studies are aimed at defining Type 2 tumors using karyotypic analyses in an effort to define unique chromosomal changes in these tumors. We also plan to use the approaches contained in the first two sections to study the relationship between Type 1 and Type 2 progressors. We are, therefore, proposing a continuation of our earlier work and Its extension to newer areas using molecular genetic techniques to assess genomic instability and tumor progression.