Molecular Changes Associated with PCa bone metastases

与 PCa 骨转移相关的分​​子变化

• 批准号: 6803233
• 负责人: KENNETH J. PIENTA
• 金额: $ 33.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-24 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6803233
• 关键词: SCID mouse; biomarker; bone neoplasms; cell line; clinical research; gene expression; genetic polymorphism; human tissue; metastasis; molecular oncology; neoplasm /cancer genetics; prostate neoplasms

DESCRIPTION (provided by applicant): In the RFA for Molecular interaction between tumor cells and bone, one area of emphasis was that "A comprehensive analysis of genetic changes occurring between primary tumor and bone metastases and the development of a tractable system to study bone metastases are needed." This application focuses on this area of emphasis by demonstrating that we have developed a method for comprehensive genetic expression analysis between both primary prostate cancer and metastatic prostate cancer but also between prostate cancer metastases that develop in bone versus soft tissue sites. This analysis has allowed us to preliminarily identify potential genes of importance that regulate prostate cancer metastasis to bone. We hypothesize that we can identify genetic changes that are important in prostate cancer metastasis to bone and determine their functional significance in prostate cancer bone metastasis. To test this hypothesis we have developed the following specific aims: Specific Aim 1: Characterize the expression signature of prostate metastases derived from bone versus soft tissue sites. Utilizing tissue acquired through our Rapid Autopsy Program, we will identify genes that are differentially expressed in prostate cancer metastases at the gene and tissue level. Specific Aim 1A: We will utilize tissue derived from multiple bone versus soft tissue sites from a variety of patients (variable genetic background). Specific Aim 1B: We will utilize tissue derived from multiple bone and soft tissue sites from a single patient (common genetic background). Specific Aim 1C: Utilize prostate cancer cell lines grown on bone matrix versus liver extracellular matrix to look at differential gene expression. Specific Aim 2: We will investigate the function of differentially expressed genes between bone and soft tissue metastases to determine their significance to prostate cancer metastasis to bone. We will start with the FROUNT/PERICENTRIN gene, identified in our preliminary experiments. Specific Aim 2A: We will study the potential significance of genes that are differentially expressed between bone and soft tissue metastases as prognostic and diagnostic markers for prostate cancer utilizing our tissue microarrays with the corresponding clinical follow-up data. In summary, we have developed an effective paradigm for identifying and characterizing genes whose expression is altered in metastatic versus primary prostate cancers. By concentrating on genetic changes between bone and soft tissue metastases, a better understanding of the molecular biology that underpins prostate cancer metastasis should be elucidated. This knowledge could lead to the development of better biomarkers of disease progression as well as targets for therapy.

描述（由申请人提供）： 在肿瘤细胞与骨骼之间的分子相互作用的RFA中，重点的一个领域是“对原发性肿瘤和骨转移之间发生的遗传变化进行了全面分析，以及需要研究骨转移的可行系统的发展”。该应用重点是这一重点，证明我们已经开发了一种在原发性前列腺癌和转移性前列腺癌之间进行全面遗传表达分析的方法，并且在骨骼与软组织部位发展的前列腺癌转移之间也是如此。该分析使我们能够初步识别调节前列腺癌转移对骨的潜在潜在基因。我们假设我们可以鉴定出在前列腺癌转移对骨骼中很重要的遗传变化，并确定它们在前列腺癌骨转移中的功能意义。为了检验这一假设，我们开发了以下特定目的：特定目的1：表征源自骨骼与软组织部位的前列腺转移的表达特征。利用通过我们的快速尸检程序获得的组织，我们将确定在基因和组织水平上在前列腺癌转移中差异表达的基因。特定目标1a：我们将利用从多个骨骼与软组织部位得出的组织（可变遗传背景）。特定目标1B：我们将利用来自单个患者的多个骨骼和软组织部位的组织（常见的遗传背景）。特定目标1C：利用在骨基质上与肝外基质在骨基质上生长的前列腺癌细胞系来查看差异基因表达。具体目标2：我们将研究骨和软组织转移之间差异表达基因的功能，以确定它们对前列腺癌转移对骨骼的重要性。我们将从我们的初步实验中确定的Frount/pericentrin基因开始。特定目标2a：我们将研究骨和软组织转移之间差异表达的基因的潜在意义，作为前列腺癌的预后和诊断标记，利用我们的组织微阵列和相应的临床随访数据。总而言之，我们开发了一种有效的范式，用于识别和表征其表达在转移性前列腺癌和原发性前列腺癌中改变的基因。通过专注于骨骼和软组织转移之间的遗传变化，可以更好地理解基于前列腺癌转移的分子生物学。这些知识可能导致疾病进展的更好的生物标志物以及治疗靶标。