The Role of Cellular Receptors Involved in Inflammation and Tumor Progression

高度恶性的人胶质母细胞瘤和间变性星形细胞瘤标本表达一种 甲酰基肽受体FPR，其通常在髓样细胞中表达，并导致其在骨髓细胞中的表达。 细菌肽诱导的趋化性和活化。人脑胶质瘤细胞系的筛选 结果显示，FPR仅在恶性度更高的胶质瘤细胞系中表达。FPR表达 在胶质母细胞瘤细胞系中介导肿瘤细胞迁移、增殖和产生 血管生成因子，血管内皮生长因子（VEGF）和IL-8（CXCL 8）， 坏死肿瘤细胞释放的激动剂分子。胶质母细胞瘤细胞中FPR的刺激 还通过信号转导激活表皮生长因子（EGFR）受体 一种增加细胞内酪氨酸残基磷酸化的级联反应， EGFR的结构域。EGFR被FPR反式激活是FPR的部分功能 介导肿瘤细胞迁移和活化。肿瘤细胞中FPR或EGFR的耗竭 通过小干扰（si）RNA，每种RNA都降低了肿瘤细胞主动形成的能力， 在裸鼠体内生长肿瘤。然而，两种受体的耗竭完全消除了 胶质母细胞瘤细胞的致瘤性。神经元异常调控机制的研究 在胶质母细胞瘤细胞中表达的FPR显示， p53基因，这降低了肿瘤细胞中p53抑制FPR的能力。这是颠倒的 通过降低p53基因启动子的甲基化和胶质母细胞瘤细胞的分化 转化为恶性程度较低的表型。因此，FPR在促进胶质母细胞瘤中起重要作用 高度恶性的人胶质母细胞瘤和间变性星形细胞瘤标本表达一种新的抗胶质母细胞瘤治疗剂的分子靶点。 甲酰基肽受体FPR，其通常在髓样细胞中表达，并导致其在骨髓细胞中的表达。 细菌肽诱导的趋化性和活化。人脑胶质瘤细胞系的筛选 结果显示，FPR仅在恶性度更高的胶质瘤细胞系中表达。FPR表达 在胶质母细胞瘤细胞系中介导肿瘤细胞迁移、增殖和产生 血管生成因子，血管内皮生长因子（VEGF）和IL-8（CXCL 8）， 坏死肿瘤细胞释放的激动剂分子。胶质母细胞瘤细胞中FPR的刺激 还通过信号转导激活表皮生长因子（EGFR）受体 一种增加细胞内酪氨酸残基磷酸化的级联反应， EGFR的结构域。EGFR被FPR反式激活是FPR的部分功能 介导肿瘤细胞迁移和活化。肿瘤细胞中FPR或EGFR的耗竭 通过小干扰（si）RNA，每种RNA都降低了肿瘤细胞主动形成的能力， 在裸鼠体内生长肿瘤。然而，两种受体的耗竭完全消除了 胶质母细胞瘤细胞的致瘤性。神经元异常调控机制的研究 在胶质母细胞瘤细胞中表达的FPR显示， p53基因，这降低了肿瘤细胞中p53抑制FPR的能力。这是颠倒的 通过降低p53基因启动子的甲基化和胶质母细胞瘤细胞的分化 转化为恶性程度较低的表型。因此，FPR在促进胶质母细胞瘤中起重要作用 是设计新型抗胶质母细胞瘤治疗剂的分子靶标。

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.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.