Mechanisms of Prostate Cancer Dormancy in the Bone Marrow Niche

前列腺癌在骨髓微环境中休眠的机制

基本信息

批准号：
8213014
负责人：
Evan T Keller
金额：
$ 54.1万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8213014
关键词：
American Apoptosis Biopsy Blood Tests Bone Marrow Cancer Etiology Cells Cessation of life Clinical Core Biopsy Development Diagnosis Disease Disease Progression Event Growth Health Hematopoietic stem cells Human Instruction Lead Legal patent Lesion Malignant Neoplasms Malignant neoplasm of prostate Marrow Metastatic Lesion Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Molecular Morbidity - disease rate Neoplasm Metastasis Operative Surgical Procedures Primary Neoplasm Proliferating Prostate Prostate-Specific Antigen Prostatectomy Radiation Radiation therapy Radical Prostatectomy Retropubic Prostatectomy Sampling Second Primary Cancers Staging Ultrasonography Work bone bone imaging cancer surgery combat digital experience innovation insight lymph nodes men mortality neoplastic cell novel therapeutics older men programs rectal skeletal disorder stem cell niche trafficking

项目摘要

DESCRIPTION (provided by applicant): Mr. W. is a 66 year old man. Six years ago he w/as diagnosed with a moderately differentiated, localized prostate cancer (PCa) when he presented for a routine physical exam and was found to have a prostate specific antigen (PSA) blood test of 5.2. Digital rectal exam revealed no abnormalities but prostate ultrasound and biopsy revealed a Gleason 4+3 = 7 cancer in 2/12 biopsy cores (clinical stage TIcNxMx). Because Mr. W. was in otherwise excellent health, he chose to undergo a radical retro pubic prostatectomy and his prostate was removed. All of his lymph nodes were negative for cancer. He was considered to be cured of his disease. One year ago, Mr. W.'s PSA became detectable and he now has 3 lesions present on bone scan. He has metastatic prostate cancer, now incurable. Each year, approximately 40,000 men who "should" have been cured of their prostate cancer by surgery or radiation therapy present with incurable metastatic disease that will manifest itself as metastatic lesions in the bone, usually years after primary treatment. The only explanation for this is that disseminated tumor cells (DTCs) are present in the bone microenvironment before surgery or radiation eradicated the primary tumor. Clearly the ability of DTCs to proliferate, undergo apoptosis or become dormant must occur soon after the initial arrest of circulating tumor cells (CTCs) in the marrow. Unquestionably, a greater understanding of the molecular events that regulate a DTCs ability to become, and remain dormant over long periods is crucial to define new therapeutic strategies to combat disease progression. How these cells traffic to the bone (Project 1), become dormant (Project 2), and then ultimately begin to proliferate (Project 3) is the subject of this TMEN application. The proposed TMEN is composed of three highly interactive and complementary projects that are supported by a Human Sample Acquisition Core (HSAC). Ultimately this work will lead to defining new therapeutic strategies to combat PCa skeletal metastases. The findings generated by this program will lead to a significant impact on the health and well being of men with PCa. The global hypothesis Is that DTCs target the hematopoietic stem cell (HSC) niche during metastasis. Once In the niche the niche regulates dormancy of DTCs. When DTCs are able to overcome the growth regulatory effects of the HSC niche, metastatic foci develop.

描述（由申请人提供）：W.先生是一位66岁的男性。六年前，当他进行常规体检时，他被诊断患有中分化局部前列腺癌 (PCa)，并发现前列腺特异性抗原 (PSA) 血液测试为 5.2。直肠指检未发现异常，但前列腺超声和活检显示 2/12 活检核心存在 Gleason 4+3 = 7 癌症（临床分期 TIcNxMx）。由于 W. 先生在其他方面的健康状况良好，因此他选择接受根治性耻骨后前列腺切除术，并切除了前列腺。他所有的淋巴结癌症呈阴性。人们认为他的病已痊愈。一年前，W. 先生的 PSA 变得可检测到，现在骨扫描显示他有 3 个病变。他患有转移性前列腺癌，目前无法治愈。每年，大约有 40,000 名男性“应该” 已通过手术或放射治疗治愈了前列腺癌转移性疾病，通常在数年后表现为骨中的转移性病变基本的治疗。对此的唯一解释是播散性肿瘤细胞（DTC）存在于手术或放疗前的骨微环境根除原发肿瘤。显然，DTC 必须在增殖、凋亡或休眠后不久就出现能力。骨髓中循环肿瘤细胞（CTC）的最初停滞。毫无疑问，更大了解调节 DTC 成为和保持休眠能力的分子事件长期的治疗对于确定新的治疗策略来对抗疾病进展至关重要。如何这些细胞运输到骨骼（项目 1），进入休眠状态（项目 2），然后最终开始 proliferate（项目 3）是该 TMEN 应用程序的主题。拟议的 TMEN 包括由人类样本支持的三个高度互动和互补的项目采集核心 (HSAC)。最终，这项工作将导致定义新的治疗策略对抗 PCa 骨骼转移。该计划产生的结果将产生重大影响对 PCa 男性健康和福祉的影响。总体假设是 DTC 在转移。一旦进入生态位，生态位就会调节 DTC 的休眠。当 DTC 能够克服 HSC 生态位的生长调节作用，形成转移灶。