The Role of Cellular Receptors Involved in Inflammation and Tumor Progression

在研究化学引诱物受体在肿瘤生长和肿瘤转移中的作用的过程中， 转移，我们发现高度恶性的人类胶质母细胞瘤和间变性星形细胞瘤， 标本对甲酰肽受体FPR染色呈阳性， 在骨髓细胞中表达，并导致其趋化性和细菌诱导的激活 缩氨酸筛选人脑胶质瘤细胞系发现FPR仅在胶质瘤中表达 具有更高恶性表型的细胞系。FPR在胶质母细胞瘤细胞系中的表达 介导肿瘤细胞的趋化性、增殖和血管生成因子的产生， 内皮生长因子（VEGF），对坏死肿瘤释放的激动剂分子的反应 细胞此外，胶质母细胞瘤细胞中FPR的刺激也激活了用于 表皮生长因子（EGFR）的信号转导级联，增加 在一些实施方案中，所述方法包括使EGFR的细胞内结构域中的选定酪氨酸残基磷酸化，并且 依赖于G蛋白，受Src酪氨酸激酶控制。EGFR的反式激活， FPR约占FPR介导肿瘤细胞迁移能力的40%， activation.通过小干扰（si）RNA分别消耗肿瘤细胞中的FPR或EGFR 降低了肿瘤细胞在裸鼠中形成活跃生长肿瘤的能力。然而，在这方面， 两种受体的耗尽完全消除了胶质母细胞瘤细胞的致瘤性。 因此，FPR在人胶质母细胞瘤中通过响应激动剂活性而异常表达 在肿瘤微环境中产生的与EGFR合作，促进快速肿瘤 进展这些结果表明，重要的分子目标的设计， 抗胶质母细胞瘤治疗。

In the course of studying the role of chemoattractant receptors in tumor growth and metastasis, we discovered that highly malignant human glioblastoma and anaplastic astrocytoma specimens were stained positively for the 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 glioma cell lines with a more highly malignant phenotype. FPR expressed in glioblastoma cell lines mediates tumor cell chemotaxis, proliferation and production of an angiogenic factor, vascular endothelial growth factor (VEGF), in response to agonist moleculaes released by necrotic tumor cells. Furthermore, 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 and is dependent on G-proteins and controlled by Src tyrosine kinase. This transactivation of EGFR by FPR accounts for approximately 40% 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. Thus, FPR aberrantly expressed in human glioblastoma by responding to agonist activity produced in the tumor microenvironment cooperates with EGFR to promote rapid tumor progression. These results suggest important molecular targets for the design of anti-glioblastoma therapeutics.