CXCR4 regulation of tumor progression in Multiple Myeloma

描述（由申请人提供）：MM的特点是在诊断时疾病广泛存在，存在多个溶解性病变和弥散性累及骨髓（BM），这意味着MM的进展涉及MM细胞在外周血中的持续循环并重新进入BM。趋化因子在淋巴细胞运输和归巢中发挥核心作用，特别是趋化因子SDF-1及其受体CXCR4以及最近发现的受体CXCR7。我们假设调节MM细胞在微环境中的生存能力将改变其生物学特性并诱导对凋亡的敏感性。特异性目的1：确定MM细胞响应SDF-1/CXCR4轴的归巢机制。我们将通过确定抑制sdf -1依赖的MM归巢的长期生物学后遗症及其对肿瘤进展的影响，确定MM细胞与其他BM微环境细胞之间归巢动力学的差异，确定体外和体内调节MM细胞对CXCR4和CXCR7的归巢的下游信号通路，以及这两种受体在MM中的信号传导差异来验证这一目标。并确定其他趋化因子受体和粘附分子在调节归巢中的作用。特异性目的2：通过鉴定MM细胞粘附于BM微环境中与外周血中发生的生物学变化，鉴定SDF-1/CXCR4与粘附分子VLA-4和LFA-1的相互作用，鉴定抑制CXCR4/CXCR7和/或粘附分子对MM细胞体内生长和存活的影响，确定SDF-1/CXCR4轴对MM细胞体外和体内的粘附和存活的影响。具体目标3：通过确定CXCR4、CXCR7、VLA-4和MMP2/9抑制剂抑制下MM细胞动员的生物学后遗症，确定MM细胞与其他骨髓细胞动员动力学的差异，确定CXCR4/CXCR7抑制下MM细胞的迁移/动员机制。并确定动员出基底膜的MM细胞是否比驻留在基底膜中的恶性细胞对细胞毒性药物的凋亡更敏感。靶向运输将导致MM治疗方法的范式转变，我们将通过诱导细胞迁移、防止归巢和粘附来改变MM细胞在其保护性骨髓微环境中的生存能力，从而增加对凋亡的敏感性。公共卫生相关性：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、粘附和进入循环中的作用。通过将骨髓瘤细胞动员出骨髓来靶向这一过程，将导致细胞毒性药物杀死细胞的灵敏度更高。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.