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

在我们之前的P01项目中，我们研究了转移性前列腺癌（PCa）的CXCR 4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CXCR 4/SDF-1途径来归巢骨骼，而且很可能使用造血干细胞（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（Anxa 2）由成骨细胞（08 s）表达，并在生态位选择中起着关键作用。解释这些观察结果的最令人信服的机制之一是（i）Anxa 2作为粘附配体，以及（ii）当HSC与Anxa 2结合时，诱导静止。我们的初步数据有力地表明，类似的分子机制在骨髓转移性前列腺癌中发挥作用。假设：转移性豌豆寄生在“小生境”中，作为向骨性的分子机制。提出以下目标：（1）确定转移性“小生境”的位置及其在肿瘤治疗中的作用。 与原发肿瘤的相互作用。亚假设：原发性（1 <$）肿瘤和转移前“小生境”之间的分子串扰有助于控制转移性PCa的归巢。我们将探讨前列腺癌骨转移灶的定位。我们将确定通过（i）i.c.在我们的原位转移模型中建立的肿瘤是否接种了相同的小生境。(iii)确定当PCa细胞处于“小生境”时，CXCR 4/RDC 1和Anxa 2 r的表达是否不同。(2)确定SDF-1和Anxa 2的表达是否是转移所必需的。亚假设：选择HSC小生境是转移所必需的。在这个目标中，我们将确定（2A）SDF-1、（28）Anxa 2的表达是否是PCa在骨中归巢/寄宿所必需的。将PCa细胞原位植入体内，并通过QPCR追踪“脱落”或播散的细胞。这种分析使我们能够识别和探索极早期的事件。(3)定义PCa和“利基”的相互作用。亚假设：PCa使用HSC小生境在骨髓中建立“立足点”。我们会的（3A）定义了SDF-1信号通路的作用，（38）一旦转移性PCa细胞已经进入小生境，Anxa 2及其受体（Anxa 2 r）作为“小生境”寄生的分子机制发挥作用。在我们最后的子目标中，我们将先前的研究与（3C）确定Anxa 2/Anxa 2 r信号传导是否通过SDF-1促进骨中的PCa生长联系起来。

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.