CXCR4 regulation of tumor progression in Multiple Myeloma

摘要 多发性骨髓瘤的特点是诊断时广泛存在的疾病，并存在多个溶血性病变和 骨髓(BM)播散性受累，意味着MM的进展涉及到持续的 外周血中MM细胞的循环和重新进入骨髓。趋化因子扮演着中心角色 在淋巴细胞的运输和归巢中，特别是趋化因子SDF-1及其受体CXCR4和 最近发现的受体CXCR7。我们假设多发性骨髓瘤细胞驻留在 它们的微环境会改变它们的生物学特性，诱导其对细胞凋亡的敏感性。具体目标1： 探讨骨髓瘤细胞对SDF-1/CXCR4轴的归巢机制。我们将通过以下方式测试这一目标 检测抑制SDF-1依赖的MM归巢的长期生物学后遗症及对其的影响 肿瘤进展，决定MM细胞和其他骨髓细胞归巢动力学的差异 微环境细胞，识别调节MM细胞归巢的下游信号通路 CXCR4和CXCR7在体外和体内的反应，以及这两种受体在MM中信号转导的差异， 以及确定其他趋化因子受体和黏附分子在归巢调节中的作用。 特异性目标2：确定SDF-1/CXCR4轴在体外和体内对黏附和存活的影响 通过鉴定附着在骨髓微环境中的MM细胞中发生的生物学变化来研究MM细胞 与外周血比较，鉴定SDF-1/CXCR4与黏附的相互作用 分子即VLA-4和LFA-1，并鉴定抑制CXCR4/CXCR7和/或黏附的作用 分子对MM细胞在体内生长和存活的影响。具体目标3：确定 测定MM细胞对CXCR4/CXCR7抑制作用的生物学效应 抑制CXCR4、CXCR7、VLA-4和MMP2/9动员MM细胞的后遗症 抑制剂，确定MM细胞动员动力学与其他骨髓相比的差异 细胞，并确定从骨髓中动员出来的MM细胞是否会通过以下方式对凋亡更敏感 细胞毒剂与驻留在骨髓中的恶性细胞的比较。打击人口贩运将导致一种范式 多发性骨髓瘤治疗方法的转变，我们将改变多发性骨髓瘤细胞驻留在其保护性细胞中的能力 骨髓微环境通过诱导排泄和防止归巢和黏附，导致 对细胞凋亡的敏感性增加。与公共卫生的相关性： 骨髓瘤的肿瘤进展机制尚不清楚。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 粘附性及其进入循环的出口。通过动员骨髓瘤细胞走出这一过程来靶向 骨髓对细胞毒剂的杀伤敏感性更高。

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.