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：
8713957
负责人：
Evan T Keller
金额：
$ 49.55万
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/8713957
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 Circulating Cells 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。先生是一个66岁的男人。六年前，他被诊断出患有适度分化的局部前列腺癌（PCA），当时他进行了常规的体格检查，并被发现患有前列腺特异性抗原（PSA）血液测试为5.2。数字直肠检查没有发现异常，但是前列腺超声检查和活检显示2/12活检核心的Gleason 4+3 = 7癌症（临床阶段TICNXMX）。由于W.先生的健康状况良好，因此他选择进行根本的复古耻骨前列腺切除术，并去除前列腺。他的所有淋巴结都对癌症阴性。他被认为治愈了他的疾病。一年前，W。先生的PSA变得可检测到，他现在在骨扫描上有3个病变。他患有转移性前列腺癌，现在无法治愈。每年，大约有40,000名“应该”的人已经通过手术或放射治疗治愈了前列腺癌通常几年后，转移性疾病会表现为骨骼中的转移性病变基本的治疗。对此的唯一解释是，散布的肿瘤细胞（DTC）存在于手术或辐射前的骨微环境消除了原发性肿瘤。显然，必须在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的分子事件，并保持休眠状态长期以来，对于定义了打击疾病进展的新的治疗策略至关重要。如何这些细胞流向骨骼（项目1），处于休眠状态（项目2），然后最终开始扩散（项目3）是此TMEN应用程序的主题。提出的TMEN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战斗PCA骨骼转移。该程序产生的发现将导致重要对患有PCA的男性的健康和健康的影响。全球假设是DTC靶向造血干细胞（HSC）生态位。转移。一旦进入利基市场，利基市场就会调节DTC的休眠。当DTC能够克服HSC利基市场的增长调节作用，转移灶的发展。