Semaphorin 4D在骨巨细胞瘤中的表达、作用及其机制的研究

Giant cell tumor of bone (GCTB) is commonly regarded as a low-grade or potential malignant tumor with unpredictable bio-behavior. The tumors show a tendency of significant bone destruction, high local recurrence, and occasionally lung metastasis. GCTB represents approximately 20% of all primary bone tumors in China. Surgical resection is the first choice of treatment for GCTB. However, postoperatively local recurrence rates reported in the previous study range from 27% to 55%, especially serious in the spine..The mechanisms of tumorigenesis and recurrence of GCTB remain still obscure. Formerly, the research topics of GCTB mainly focused on a minority of interesting proteins and or genes. semaphorin 4D (Sema4D) is widely distributed in the nervous system and lymphatic system. However, it is a relative novel factor plays important roles in musculoskeletal system. Sema4D regulate cell adhesion, proliferation, migration and morphological during tumor growth and metastasis, and play an important role in the immune response and angiogenesis. Sema4D-deficient primary osteoclasts showed impaired spreading, adhesion, migration and resorption due to altered ?3 integrin sub-unit downstream signaling. It seems that Sema4D may be an important biological regulatory of GCTB malignant phenotype. Therefore, this project will discover the roles that Sema4D played in GCTB in effect and it's mechanism research, provide an important diagnostic marker for the clinical classification of GCTB and it's malignant, on this basis we will find effective interventions that help the clinical treatment of GCTB both theoretically and technically.

骨巨细胞瘤（ GCTB），是一种有低度恶性潜能的肿瘤，它可以表现出侵袭性的特点，也可以出现肿瘤原发部位顽固性生长以及转移，GCTB恶变是其高复发率、致残率、致死率的重要原因。GCTB在中国人群中发病率较高，占全部原发骨肿瘤的18.4%。但是，目前临床上缺乏能够准确判断GCTB预后、复发、转移的分型系统。因此，寻找与GCTB相关的生物学表型具有重要的理论意义及临床价值。Semaphorin4D（Sema4D）是一种在神经系统、肌肉骨骼系统中广泛分布的细胞因子，调节细胞粘附、增殖、迁移及形态变化，在肿瘤生长转移、免疫反应及血管生成的过程中起到重要作用。Sema4D可能是调节GCTB恶变的重要生物学表型。因此，本项目将对Sema4D在GCTB中的作用及其机制进行研究，以期为GCTB恶变的临床分型提供重要的诊断指标，并在此基础上寻找有效地干预措施，为GCTB的临床治疗提供理论依据和技术方法。

GCTB是一种潜在侵袭的肿瘤，有较强的局部侵袭性，易复发。对于骨盆、脊柱等复杂部分的GCTB，扩大刮除和瘤段切除都难以做到，物理或化学辅助治疗处理也因恐伤及病灶周围重要的神经血管组织而受限，GCTB复发率难以明显降低，目前临床上对GCTB没有损伤较小的治疗方法，GCTB中含有两种主要细胞成分：基质细胞与多核巨细胞，造成了GCTB复杂的生物学表现，但是对GCTB中基质细胞与多核巨细胞相互间关系的研究较少。本课题主要研究Semaphorin4D（Sema4D）对GCTB影响，并在裸鼠GCTB模型上使用anti-Sema4D进行干预。研究进展顺利，已按计划完成预期任务。研究结果提示Sema4D在GCTB中高表达，但是初发、复发二者无明显差别；给予anti-Sema4D可阻断体外培养的多核巨细胞发生融合，干扰细胞骨架形成，同时发现给予anti-Sema4D可降低Roh-ROCK通路活性；体外给予anti-Sema4D可抑制骨巨细胞瘤的生长，但是给予Sema4D并不能起到促进作用。本项目完成了Sema4D在GCTB组织中表达、对不同细胞的作用机制以及anti-Sema4D对GCTB治疗效果的研究，提示Sema4D可能在GCTB治疗中发挥重要调节作用，相关研究成果已投稿。