CXCR4 regulation of tumor progression in Multiple Myeloma

摘要 MM的特征是诊断时疾病广泛，存在多发性溶解性病变， 骨髓（BM）的弥散性受累，这意味着MM的进展涉及持续的 MM细胞在外周血中的循环并重新进入BM。趋化因子起着核心作用 在淋巴细胞运输和归巢中，特别是趋化因子SDF-1及其受体，CXCR 4沿着 最近发现的受体CXCR 7。我们假设调节MM细胞的能力， 它们的微环境将改变它们的生物学特性并诱导对凋亡的敏感性。具体目标1： 确定MM细胞响应SDF-1/CXCR 4轴归巢的机制。我们将通过以下方式来检验这一目标： 确定抑制MM的SDF-1依赖性归巢的长期生物学后遗症及其对 肿瘤进展，确定MM细胞和其他BM之间归巢动力学的差异 微环境细胞，确定调节MM细胞归巢的下游信号通路， 体外和体内对CXCR 4和CXCR 7的反应，以及MM中这两种受体信号传导的差异， 以及鉴定其他趋化因子受体和粘附分子在归巢调节中的作用。 具体目的2：确定SDF-1/CXCR 4轴对粘附和存活的体外和体内作用 通过鉴定粘附于BM微环境的MM细胞中发生的生物学变化， 与外周血相比，鉴定SDF-1/CXCR 4与粘附的相互作用， 分子，即VLA-4和LFA-1，并鉴定CXCR 4/CXCR 7和/或粘附的抑制作用 分子对MM细胞在体内的生长和存活的影响。具体目标3：确定 通过测定MM细胞对CXCR 4/CXCR 7抑制的生物学应答， MM细胞对CXCR 4、CXCR 7、VLA-4和MMP 2/9抑制的动员反应的后遗症 抑制剂，确定MM细胞动员动力学与其他骨髓抑制剂相比的差异 细胞，并确定从BM中动员出来的MM细胞是否对细胞凋亡更敏感， 与存在于BM中的恶性细胞相比，细胞毒性剂。打击贩运将导致一种范例 MM治疗方法的转变，我们将改变MM细胞驻留在其保护性细胞中的能力， 通过诱导外排和防止归巢和粘附来改变骨髓微环境， 增加对凋亡的敏感性。与公共卫生的相关性： 骨髓瘤中肿瘤进展的机制尚未完全了解。我们将研究 趋化因子SDF-1及其受体在调节骨髓瘤细胞进入骨髓中的作用， 粘附并进入循环。通过将骨髓瘤细胞从骨髓中动员出来， 骨髓将导致对细胞毒性剂杀死细胞的更高敏感性。

Abstract MM is characterized by widespread disease at diagnosis with the presence of multiple lytic lesions and disseminated involvement of the bone marrow (BM), implying that the progression of MM involves a continuous circulation of the MM cells in the peripheral blood and re-entrance into the BM. Chemokines play a central role in lymphocyte trafficking and homing, specifically the chemokine SDF-1, and its receptors, CXCR4 along with the recently identified receptor CXCR7. We hypothesize that modulation of the capacity of MM cells to reside in their microenvironment will change their biologic properties and induce sensitivity to apoptosis. Specific Aim 1: To identify mechanisms of homing of MM cells in response to the SDF-1/CXCR4 axis. We will test this aim by determining the long-term biological sequelae of inhibition of SDF-1-dependent homing of MM and its effect on tumor progression, determining the differences in kinetics of homing between MM cells and other BM microenvironment cells, identifying the downstream signaling pathways that regulate MM cells' homing in response to CXCR4 and CXCR7 in vitro and in vivo, and difference in signaling of these two receptors in MM, and identifying the role of other chemokine receptors and adhesion molecules in the regulation of homing. Specific Aim 2: To determine the in vitro and in vivo effects of the SDF-1/CXCR4 axis on adhesion and survival of MM cells by identifying the biological changes that occur in MM cells adherent to the BM microenvironment compared to those in the peripheral blood, identifying the interaction of SDF-1/CXCR4 with adhesion molecules namely VLA-4 and LFA-1, and identifying the effect of inhibition of CXCR4/CXCR7 and/or adhesion molecules on growth and survival of MM cells in vivo. Specific Aim 3: To identify mechanisms of egression/mobilization of MM cells in response to CXCR4/CXCR7 inhibition by determining the biological sequelae of mobilization of MM cells in response to inhibition of CXCR4, CXCR7, VLA-4 and MMP2/9 inhibitors, determining the difference in kinetics of mobilization of MM cells compared to other bone marrow cells, and determining whether MM cells mobilized out of the BM will be more sensitive to apoptosis by cytotoxic agents compared to malignant cells residing in the BM. Targeting trafficking will lead to a paradigm shift in therapeutic approaches in MM, where we will alter the capacity of MM cells to reside in their protective bone marrow microenvironment by inducing egression and preventing homing and adhesion, leading to increased sensitivity to apoptosis. Relevance to Public Health: The mechanisms of tumor progression in myeloma are not well understood. We will study the role of the chemokine SDF-1 and its receptors in the regulation of entry of myeloma cells into the bone marrow, their adhesion and their exit into the circulation. Targeting this process by mobilizing myeloma cells out of the marrow will lead to a higher sensitivity to killing of the cells with cytotoxic agents.