Mechanisms of Prostate Cancer Dormancy in the Bone Marrow Niche

个人描述(申请人提供)：W.先生，66岁。六年前，当他进行常规体检时，被诊断出患有中分化局限性前列腺癌(PCA)，并被发现进行了前列腺特异性抗原(PSA)血液测试，结果为5.2。直肠指诊未发现异常，但前列腺超声和活检发现Gleason 4+3=7癌，其中2/12个活检点(临床分期为TIcNxMx)。由于W.在其他方面的健康状况很好，他选择了根治性的耻骨后前列腺切除术，并摘除了他的前列腺。他所有的淋巴结癌都是阴性。他的病被认为已经治好了。 一年前，W.‘S先生的PSA被检测出来，现在他的骨骼扫描显示有3个病变。 患有转移性前列腺癌，现在是无法治愈的。每年，大约有40,000名男性“应该” 通过手术或放射治疗治愈前列腺癌，目前患有不治之症 一种转移性疾病，通常在数年后表现为骨转移灶 主要 治疗。对此的唯一解释是播散性肿瘤细胞(DTC)存在于 术前或放疗前的骨微环境对原发灶均有清除作用。 显然，树突状细胞增殖、凋亡或休眠的能力必须在不久之后发生 骨髓中循环中的肿瘤细胞(CTCs)的最初停止。毫无疑问，一个更大的 了解调节DTC进入和保持休眠能力的分子事件 对于确定新的治疗策略以抗击疾病进展至关重要。多么 这些细胞流向骨骼(项目1)，进入休眠状态(项目2)，然后最终开始 增殖体(项目3)是本TMAN申请的主题。建议的土木工程署由下列人士组成： 三个由人类样本支持的高度互动性和互补性的项目 收购核心(HSAC)。最终，这项工作将导致定义新的治疗策略 与前列腺癌骨骼转移作斗争。该计划产生的调查结果将导致显著的 对患有前列腺癌的男性的健康和福祉的影响。 全球假说是DC在体内以造血干细胞(HSC)为靶点 转移。一旦进入小生境，小生境就会调节DTC的休眠。当DTC能够 克服HSC利基的生长调节作用，形成转移灶。

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.