The Role of Cellular Receptors Involved in Inflammation and Tumor Progression

高度恶性的人类胶质母细胞瘤和间变性星形细胞瘤标本表达甲酰基肽受体FPR，该受体通常在髓细胞中表达，并导致髓细胞被细菌肽诱导趋化和活化。对胶质瘤细胞系的筛选表明，FPR仅在恶性程度较高的胶质瘤细胞系中表达。胶质母细胞瘤细胞系中表达的FPR响应坏死肿瘤细胞释放的激动剂分子，介导肿瘤细胞迁移、增殖和血管生成因子、血管内皮生长因子（VEGF）和IL-8 （CXCL8）的产生。胶质母细胞瘤细胞中FPR的刺激也通过信号转导级联激活表皮生长因子（EGFR）受体，该级联可增加EGFR胞内区域中选定的酪氨酸残基的磷酸化。FPR对EGFR的这种反激活部分解释了FPR介导肿瘤细胞迁移和激活的能力。通过小干扰（si） RNA消耗肿瘤细胞中的FPR或EGFR均降低了裸鼠肿瘤细胞形成活跃生长肿瘤的能力。然而，这两种受体的消耗完全消除了胶质母细胞瘤细胞的致瘤性。对胶质母细胞瘤细胞中FPR异常表达调控的机制研究显示，p53基因启动子区域甲基化增加，从而降低了p53在肿瘤细胞中抑制FPR的能力。这被p53基因启动子甲基化的减少和胶质母细胞瘤细胞分化为较轻的恶性表型所逆转。因此，FPR在促进胶质母细胞瘤进展中起着重要作用，是设计新型抗胶质母细胞瘤治疗方法的分子靶点。

Highly malignant human glioblastoma and anaplastic astrocytoma specimens express a formylpeptide receptor FPR, which is normally expressed in myeloid cells and results in their chemotaxis and activation induced by bacterial peptides. Screening of human glioma cell lines revealed that FPR was expressed only in more highly malignant glioma cell lines. FPR expressed in glioblastoma cell lines mediates tumor cell migration, proliferation and production of angiogenic factors, vascular endothelial growth factor (VEGF) and IL-8 (CXCL8), in response to agonist molecules released by necrotic tumor cells. Stimulation of FPR in glioblastoma cells also activates the receptor for epidermal growth factor (EGFR) by a signal transduction cascade that increases the phosphorylation of a selected tyrosine residue in the intracellular domain of EGFR. This transactivation of EGFR by FPR accounts for part of the capacity of FPR to mediate tumor cell migration and activation. Depletion of either FPR or EGFR in tumor cells by small interference (si) RNA each reduced the capacity of the tumor cells to form actively growing tumors in nude mice. However, depletion of both receptors completely abolishes the tumorigenicity of glioblastoma cells. Mechanistic studies of the regulation of aberrantly expressed FPR in glioblastoma cells revealed increased methylation in the promoter region of p53 gene, which reduced the capacity of p53 to repress FPR in tumor cells. This was reversed by reduction of methylation in p53 gene promoter and differentiation of glioblastoma cells into lesser malignant phenotype. Thus, FPR plays an important role in promoting glioblastoma progression and is a molecular targets for the design of novel anti-glioblastoma therapeutics.