The Role of Cellular Receptors Involved in Inflammation and Tumor Progression

在研究趋化受体在肿瘤生长和转移中的作用的过程中，我们发现高度恶性的人胶质母细胞瘤和间变性星形细胞瘤标本的甲酰肽受体FPR染色呈阳性，该受体在髓系细胞中正常表达，并导致其在细菌肽诱导下的趋化和激活。对人脑胶质瘤细胞系的筛选表明，只有恶性表型较高的胶质瘤细胞系才有fpr的表达。在胶质母细胞瘤细胞系中表达的FPR介导肿瘤细胞的趋化、增殖和血管生成因子血管内皮生长因子(VEGF)的产生，以响应坏死肿瘤细胞释放的激动剂分子。此外，刺激胶质母细胞瘤细胞中的FPR还通过一系列信号转导通路激活表皮生长因子受体(EGFR)，该信号转导通路增加了EGFR胞内结构域中特定酪氨酸残基的磷酸化，并依赖于G蛋白，受Src酪氨酸激酶控制。这种由fpr反式激活的EGFR约占fpr介导肿瘤细胞迁移和激活能力的40%。通过小干扰(Si)RNA耗尽肿瘤细胞中的FPR或EGFR，都会降低肿瘤细胞在裸鼠体内形成活跃生长肿瘤的能力。然而，这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，在人类胶质母细胞瘤中，通过对肿瘤微环境中产生的激动剂活性的反应，FPR异常表达，并与EGFR合作，促进肿瘤的快速发展。这些结果为抗胶质母细胞瘤治疗药物的设计提供了重要的分子靶点。

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.