The Role of CXCL12 (SDF-1)/CXCR4 in Pathological Angiogenesis and Osteolytic Bone Disease in Multiple Myeloma

CXCL12 (SDF-1)/CXCR4 在多发性骨髓瘤病理性血管生成和溶骨性骨疾病中的作用

• 批准号: nhmrc : 453495
• 负责人: A/Pr Daniel Peet
• 金额: $ 44.4万
• 依托单位: The University of Adelaide
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2007
• 资助国家: 澳大利亚
• 起止时间: 2007-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/role-cxcl12-sdf-multiple-myeloma/80774
• 关键词: Role; CXCL12; SDF; CXCR4; Pathological

Multiple myeloma (MM) is the second most common haematological (or blood) cancer in western countries and is unique amongst blood cancers in its capacity to destroy the skeleton. MM is a cancer of plasma cells, which in their normal non-cancerous form, reside in lymph nodes and produce antibodies against infectious agents. When they become cancerous, they migrate or home to congenial sites within the bone marrow (BM). This directed movement or homing occurs under the influence of a chemokine molecule called CXCL12 which acts as a calling card for plasma cells to leave the lymph node and migrate to the BM. Once within the BM, the cells rapidly grow in response to BM-derived growth factors. This rapid growth causes a depletion in oxygen availability within the tumour and it becomes hypoxic. In response to this hypoxia, the tumour expresses a gene called hypoxia-inducible factor-1 (HIF-1) which regulates the expression of many proteins, including the chemokine CXCL12. Our studies show that the abnormal expression of CXCL12 by the plasma cells acts to promote blood vessel formation within the tumour, which in turn leads to greater tumour growth. In addition, our studies suggest that abnormal CXCL12 expression also promotes the recruitment and activation of large numbers of osteoclast (OC) precursors form the peripheral blood. OC are cells which normally remove unwanted or damaged bone. This proposal will study the interplay between HIF and CXCL12 in the establishment and development of MM and the associated bone destruction.

多发性骨髓瘤（MM）是西方国家第二常见的血液（或血液）癌症，并且在血液癌症中具有破坏骨骼的能力。MM是浆细胞的癌症，其以其正常的非癌形式存在于淋巴结中并产生针对感染因子的抗体。当它们癌变时，它们迁移或回到骨髓（BM）内的适宜部位。这种定向运动或归巢在称为CXCL 12的趋化因子分子的影响下发生，CXCL 12充当浆细胞离开淋巴结并迁移到BM的名片。一旦在BM内，细胞响应于BM衍生的生长因子而快速生长。这种快速生长导致肿瘤内的氧气供应耗尽，并且变得缺氧。作为对这种缺氧的反应，肿瘤表达一种称为缺氧诱导因子-1（HIF-1）的基因，该基因调节许多蛋白质的表达，包括趋化因子CXCL 12。我们的研究表明，浆细胞CXCL 12的异常表达促进了肿瘤内的血管形成，这反过来又导致了更大的肿瘤生长。此外，我们的研究表明，CXCL 12表达异常也促进了外周血中大量破骨细胞（OC）前体的募集和活化。OC是通常去除不需要的或受损的骨的细胞。本研究旨在探讨HIF和CXCL 12在MM的发生、发展及相关骨破坏中的相互作用。