Myeloma-Microenvironment Interaction Dynamics

这项拟议的研究旨在阐明骨髓(BM)微环境中的各种细胞在多发性骨髓瘤(MM)发病机制中的作用。多发性骨髓瘤是一种曾经罕见但日益常见的血液系统恶性肿瘤，目前在美国每年有近1.4万人受到影响。尽管治疗取得了进步，多发性骨髓瘤仍然无法治愈。中心假设是，骨髓瘤细胞改变了骨髓微环境中的细胞和细胞因子环境，从而有利于它们的生长和生存。我们将确定支持多发性骨髓瘤生长的关键细胞成分，以及可能抑制肿瘤生长的其他细胞类型。我们最近开发了治疗原发人类骨髓瘤的SCID-HU宿主系统。在这个活体系统中，原代骨髓瘤细胞只在人类骨髓环境中生长。与患者一样，骨髓瘤细胞与人类骨髓微环境的相互作用与典型的多发性骨髓瘤症状相关，为研究这种相互作用机制提供了一个极好的工具。在本研究中，我们将集中讨论破骨细胞和成骨细胞在多发性骨髓瘤发病过程中的作用。我们的具体目标包括以下几个方面：具体目标1：阐明骨髓瘤细胞和破骨细胞之间的相互关系。骨髓瘤细胞可诱导破骨细胞生成。我们将通过用破骨细胞抑制剂治疗携带骨髓瘤的SCID-HU宿主来测试破骨细胞活性是否对原发骨髓瘤的生长是必需的。使用体外和体内两种方法，我们还将测试分离的破骨细胞支持骨髓瘤生长的能力。具体目标2：揭示骨髓瘤细胞和成骨细胞相互影响的分子机制。我们假设成骨细胞产生干扰骨髓瘤生长的因子。我们将在体外和SCID-HU宿主中测试成骨细胞影响骨髓瘤细胞生长和存活的能力。我们还将检测骨髓瘤细胞对骨髓瘤成骨细胞存活的影响，并检测这些细胞对间充质干细胞分化途径的影响。通过这项研究的结论，本研究将确定破骨细胞活性增加对骨髓瘤细胞生长和存活的重要性，以及干预骨髓瘤诱导的破骨细胞生成是否可以预防和控制MM。它还将确定成骨细胞在MM中的参与，以及骨髓瘤骨骼中骨形成的增加是否会影响骨髓瘤的进展。这项研究将有助于开发一种有效的治疗多发性骨髓瘤患者或其风险，以及它的预防。

The proposed research seeks to elucidate the roles of various cells in the bone marrow (BM) microenvironment in the pathogenesis of multiple myeloma (MM), a once rare but increasingly more common hematologic malignancy that currently afflicts nearly 14,000 people in the U.S. each year. Despite treatment advances, MM remains incurable. The central hypothesis is that myeloma cells alter the cellular and cytokine milieu in the BM microenvironment to their growth and survival advantage. We will identify cellular elements critical for supporting the growth of MM, as well as other cell types that may restrain tumor growth. We recently developed the SCID-hu host system for primary human myeloma. In this in vivo system, primary myeloma cells grow exclusively in a human BM environment. As in patients, interaction of myeloma cells with the human BM microenvironment is associated with typical MM manifestations, providing an excellent tool for studying this interaction mechanism. In this study, we will concentrate on the role of osteoclasts and osteoblasts in the MM disease process. Our Specific Aims include the following: Specific Aim 1: Elucidate the reciprocal relationship between myeloma cells and osteoclasts. Myeloma cells induce osteoclastogenesis. We will test whether osteoclast activity is required for the growth of primary myeloma by treating myeloma-bearing SCID-hu hosts with osteoclast inhibitors. Using both in vitro and in vivo approaches, we will also test the ability of isolated osteoclasts to support myeloma growth. Specific Aim 2: Unravel the molecular mechanisms by which myeloma cells and osteoblasts affect each other. We hypothesize that osteoblasts produce factors that interfere with myeloma growth. We will test the ability of osteoblasts to affect the growth and survival of myeloma cells in vitro and in SCID-hu hosts. We will also test the effect of myeloma cells on the survival of osteoblasts in myelomatous bone, and examine the effect of these cells on the differentiation pathways of mesenchymal stem cells. By its conclusion, work under this study will have determined the importance of increased osteoclast activity to myeloma cell growth and survival, and whether interfering with myeloma-induced osteoclastogenesis will prevent and control MM. It will also have determined the involvement of osteoblasts in MM, and whether increasing bone formation in myelomatous bones will affect myeloma progression. This study will help develop an effective treatment for patients with MM or at risk of it, as well as its prevention.