HUMAN PROSTATE CANCER NUCLEI--STRUCTURE ABNORMALITIES AND NEW MOLECULAR MARKERS

人类前列腺癌核——结构异常和新分子标记

• 批准号: 6203264
• 负责人: DONALD straley COFFEY
• 金额: $ 16.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-04 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6203264
• 关键词: DNA directed DNA polymerase; cell nucleus; enzyme activity; fine needle aspiration; genetic markers; human tissue; laboratory rat; neoplasm /cancer diagnosis; neoplasm /cancer genetics; nuclear matrix; prostate neoplasms; technology /technique development; telomere; tissue /cell culture

There is an urgent need for new ways to assess the biological properties of prostate cancers that can be applied to needle biopsies. This research program will identify new molecular markers of human prostate cancer as new diagnostic and prognostic factors for clinical translation to the outcome for individual patients. These molecular markers will be correlated with the response and biological properties of prostate cancer such as structure, growth immortalization, invasion, and metastasis. Studies will focus on cell structural alterations, DNA instability and telomerase activity that are applicable to zonal analysis of needle biopsies. Alterations in nuclear and cellular shapes have long been recognized as one of the very earliest and most common cellular events associated with any type of carcinogenesis, This morphological transformation involves variation in nuclear morphology and chromatin patterns that are distinguishing features in the cytopathological identification of cancer cells. We have correlated quantitative morphometry of nuclear and chromatin changes with prognosis in human prostate cancer, and propose here to identify their molecular components, The shape of the nucleus appears to be defined by an internal nuclear scaffolding system that forms an organizing framework that we termed the nuclear matrix. The nuclear matrix provides a tissue specific 3- dimensional organization of DNA that dictates the higher order structure of the genome. The protein components of the matrix are tissue- and tumor-specific and provide DNA binding sites that define the spatial locations for tissue specific gene expression with actively expressed genes located on the nuclear matrix. DNA synthesis occurs at fixed replicating sites located near these matrix attachment sites. Telomeres are tightly attachments to the nuclear matrix. The nuclear matrix is ideally positioned to play a critical role in providing structural sites for organizing many nuclear events involved in DNA functions. Therefore, in carcinogenesis and tumor progression, the aberrations seen in the shapes of the cancer nuclei may be of prime importance in disturbing normal DNA functions that are organized on the nuclear matrix. We have observed specific changes occurring in nuclear matrix proteins associated with prostate cancer in both humans and animals. A new matrix protein, PC-1, appears in human prostate cancer, while other matrix proteins like NBP-4, disappear, Antibodies have been made to these proteins that will assist in their evaluation. We have also observed shortening in telomere lengths in human prostate cancer that accompanies induction of telomerase activity. These nuclear matrix proteins and telomerase activity will be applied to needle biopsies and translated into clinical evaluation.

目前迫切需要新的方法来评估生物 前列腺癌的性质，可以适用于针 活组织检查 这项研究计划将确定新的分子 作为新的诊断和预后的人前列腺癌标志物 临床转化为个体结局的因素 患者这些分子标记将与 前列腺癌的反应和生物学特性， 结构、生长永生化、侵袭和转移。 研究将集中在细胞结构改变，DNA不稳定性 和端粒酶活性，适用于区域分析 穿刺活检 细胞核和细胞形态的改变 长期以来被认为是最早和最常见的 与任何类型的致癌作用相关的细胞事件， 形态转化涉及核内的变异 形态学和染色质模式是区别特征 在癌细胞的细胞病理学鉴定中。 我们有 核和染色质的相关定量形态计量学 在人类前列腺癌的预后变化，并提出在这里 来鉴定它们的分子组成，细胞核的形状 似乎是由内部核支架系统定义的 形成了一个我们称之为核的组织框架， 矩阵 核基质提供组织特异性3- DNA的三维组织决定了更高的秩序 基因组的结构。 基质的蛋白质成分是 组织和肿瘤特异性，并提供DNA结合位点， 定义组织特异性基因表达的空间位置 在核基质上有活跃表达的基因。 DNA 合成发生在位于这些区域附近的固定复制位点上， 基质附着位点。 端粒是紧密附着在 核基质 核基质的位置非常适合 在为组织许多 核事件参与DNA功能。 因此在 癌的发生和肿瘤的进展，畸变中看到的， 癌细胞核的形状可能在 扰乱了细胞核上正常的DNA功能 矩阵 我们已经观察到发生在核中的特定变化， 与人类前列腺癌相关的基质蛋白， 动物 人前列腺中出现一种新的基质蛋白PC-1 癌症，而其他基质蛋白，如NBP-4，消失， 针对这些蛋白质的抗体已经被制造出来， 他们的评价。 我们还观察到端粒缩短 人前列腺癌中的长度，伴随着诱导 端粒酶活性 这些核基质蛋白和端粒酶 活动将应用于针活检，并转化为 临床评价