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

• 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
• 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

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。他是一位66岁的男性，六年前，当他进行常规体检时，他被诊断患有中度分化的局限性前列腺癌（PCa），并且发现前列腺特异性抗原（PSA）血液测试为5.2。直肠指检显示无异常，但前列腺超声和活检显示2/12个活检芯中的Gleason 4+3 = 7癌症（临床分期TIcNxMx）。因为W先生。在其他健康状况良好的情况下，他选择接受根治性耻骨后切除术，并切除了前列腺。他所有的淋巴结都没有癌症。人们认为他的病已经治好了. 一年前，W。的PSA变得可检测，他现在在骨扫描上有3处病变。他 患有转移性前列腺癌，现已无法治愈每年，大约有40，000名“应该” 已经通过手术或放射治疗治愈了他们的前列腺癌， 转移性疾病，将表现为骨转移性病变，通常在数年后 初级 治疗对此的唯一解释是播散性肿瘤细胞（DTC）存在于肿瘤细胞中。 手术前或放疗前的骨微环境根除了原发肿瘤。 显然，DTC增殖、凋亡或休眠的能力必须在细胞凋亡后不久发生。 骨髓中循环肿瘤细胞（CTC）的初始停滞。毫无疑问， 了解调节DTC休眠和保持休眠能力的分子事件 对于确定新的治疗策略以对抗疾病进展至关重要。如何 这些细胞向骨骼传输（项目1），进入休眠状态（项目2），然后最终开始 Proliferate（项目3）是TMEN申请的主题。拟议的TMEN由以下人员组成： 由人类样本支持的三个高度互动和互补的项目 收购核心（HSAC）。最终，这项工作将导致定义新的治疗策略， 对抗前列腺癌骨转移。该计划产生的结果将导致一个重大的 对前列腺癌患者的健康和福祉的影响。 总体假设是DTC靶向造血干细胞（HSC）小生境， 转移一旦进入生态位，生态位调节DTC的休眠。当DTC能够 克服HSC小生境的生长调节作用，转移灶形成。