Prostate Cancer Parasitism of the HSC "niche" as a Molecular Mechanism for Ost

前列腺癌 HSC“生态位”的寄生作为 Ost 的分子机制

基本信息

批准号：
8377419
负责人：
RUSSELL S TAICHMAN
金额：
$ 22.02万
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：
2004
资助国家：
美国
起止时间：
2004-06-05 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8377419
关键词：
ANXA2 gene Accounting Adhesions Angiogenic Switch Animals Antibodies Area Binding Biological Assay Biology Bone Marrow Bone Marrow Transplantation CXC Chemokines CXCR4 Receptors CXCR4 gene Cells Data Endothelial Cells Engraftment Event Foundations Funding Growth Hematopoietic stem cells Home environment Homing Homing Behavior Implant Indium Invaded Investigation Ligands Link Location Malignant Neoplasms Malignant neoplasm of prostate Marrow Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Neoplasm Metastasis Osteoblasts Pathway interactions Peptides Pisum sativum Play Primary Neoplasm Prostate Receptor Signaling Role Route Signal Pathway Signal Transduction Skeleton Stromal Cell-Derived Factor 1 Testing Therapeutic Intervention Time Tissues Work bone cancer cell cell growth foot in vivo metastatic process neoplastic cell novel parasitism receptor stem cell niche tumor

项目摘要

In our previous P01 project we examined the relationship between the expression of CXCR4 by metastatic prostate cancers (PCa) and their bone homing behavior. From these studies we acquired data that suggest that not only do PCa's use the CXCR4/SDF-1 pathway to home to bone - but there is a strong likelihood they use the hematopoietic stem cell (HSC) "niche" itself to colonize the skeleton. Here our work in this field has demonstrated that annexin II (Anxa2) expressed by osteoblasts (08s) and plays a critical role in niche selection. Among the most compelling mechanisms to account for these observations are either that (i) Anxa2 acts as an adhesion ligand, and (ii) when HSCs bind to Anxa2, quiescence is induced. Our preliminary data strongly suggests that similar molecular mechanisms are functional in metastatic PCa in the marrow. Hypothesis: Metastatic pea parasitizes the 'niche' as a molecular mechanism for osteotropism. The following aims are proposed: (1) Define the location of the metastatic 'niche' and its interactions with primary tumors. Sub hypothesis: Molecular cross talk between a primary (1¿) tumor and the premetastatic 'niche' helps to govern the homing of metastatic PCa. We will explore the localization of PCa metastatic niche in bone. We will determine where PCa cells injected by an (i) i.c. route localize in marrow and (ii) whether the same niche is seeded by tumors established in our orthotopic metastasis model. (iii) Determine if the expression of CXCR4/RDC1 and Anxa2r is different when PCa cells are in the 'niche'. (2) Determine whether expression of SDF-1 and Anxa2 by the 'niche' is essential for metastasis. Sub hypothesis: Co-opting the HSC niche is essential for metastasis. In this aim we will determine if the expression of (2A) SDF-1, (28) Anxa2 are essential for homing/lodging of PCa in bone. PCa cells are implanted in vivo orthotopically and 'shed' or disseminated cells are tracked by QPCR. This assay allows us to identify and explore extremely early events. (3) Define the interaction(s) of PCa and the 'niche'. Sub hypothesis: PCa use the HSC niche to establish a 'foot hold' in the marrow. We will; (3A) define the role that SDF-1 signaling pathways, (38) Anxa2 and its receptor (Anxa2r) playas molecular mechanisms for 'niche' parasitism once metastatic PCa cells have entered the niche. In our final sub aim, we will link the previous studies to (3C) determine if Anxa2/Anxa2r signaling facilitates PCa growth in bone via SDF-1.

在我们之前的 P01 项目中，我们研究了转移性前列腺癌 (PCa) 的 CXCR4 表达与其骨归巢行为之间的关系，从这些研究中我们获得的数据表明 PCa 不仅使用 CXCR4/SDF-1 途径回家。骨骼 - 但他们很可能利用造血干细胞（HSC）“生态位”本身来定殖骨骼，我们在这一领域的工作已经证明膜联蛋白 II。 (Anxa2) 由成骨细胞 (08s) 表达，并在生态位选择中发挥关键作用，解释这些观察结果的最引人注目的机制是 (i) Anxa2 充当粘附配体，以及 (ii) 当 HSC 与 Anxa2 结合时。我们的初步数据强烈表明，类似的分子机制在骨髓中的转移性 PCa 中发挥着作用。假设：转移性豌豆寄生于“生态位”作为一种分子机制。提出以下目标：（1）定义转移“利基”的位置及其。子假设：原发性 (1¿) 肿瘤和转移前“微环境”之间的分子串扰有助于控制转移性 PCa 的归巢。我们将确定 PCa 转移微环境的定位。通过 (i) 注射途径注射的 PCa 细胞定位于骨髓中，以及 (ii) 是否由我们的原位转移模型中建立的肿瘤播种。当 PCa 细胞处于“生态位”时，CXCR4/RDC1 和 Anxa2r 的表达不同。 (2) 确定“生态位”中的 SDF-1 和 Anxa2 表达是否对于转移至关重要。子假设：选择 HSC 生态位。在此目的中，我们将确定 (2A) SDF-1、(28) Anxa2 的表达是否对于 PCa 在骨中的归巢/停留至关重要。 PCa 细胞原位植入体内，并通过 QPCR 跟踪“脱落”或播散的细胞。该测定使我们能够识别和探索极早期的事件 (3) 定义 PCa 和“子假设”的相互作用。：PCa 使用 HSC 生态位在骨髓中建立“立足点”；我们将 (3A) 定义 SDF-1 信号通路、(38) Anxa2 及其受体 (Anxa2r) 的作用。一旦转移性 PCa 细胞进入利基，我们将发挥“利基”寄生的分子机制。在我们的最终子目标中，我们将把之前的研究与 (3C) 联系起来，确定 Anxa2/Anxa2r 信号是否通过 SDF-1 促进骨中 PCa 的生长。