Microglia facilitate glioma progression through the Pyk2 and FAK signaling

胶质母细胞瘤预后极差，中位生存期约一年。 在确诊后。胶质瘤的治疗耐药性和侵袭性否定了 目前的医学方法。小胶质细胞渗入大多数胶质瘤并释放影响肿瘤生长的因子 和入侵。研究表明，小胶质细胞释放的可溶性因子可促进细胞的迁移、增殖和 培养的胶质瘤细胞系对应用化疗的抗药性。在此之前，我们证明了小胶质细胞 通过Pyk2信号通路促进胶质瘤细胞的扩散。我们的初步数据显示， 药物抑制PYK2/FAK抑制脑胶质瘤细胞增殖并增强其细胞毒作用 替莫唑胺在小胶质细胞存在时。我们假设小胶质细胞释放因子促进 迁移、增殖、化疗耐药和肿瘤复发通过Pyk2/FAK通路。这个 使用Pyk2/FAK阻滞剂将减少小胶质细胞对肿瘤生长、扩散、复发和 对治疗的抗拒。Pyk2/FAK抑制剂联合化疗的联合治疗 化合物有可能提供显著的治疗益处。 在本研究中，我们将利用切除的人胶质母细胞瘤组织和细胞生物学方法 探讨促进小胶质细胞激活的胶质瘤侵袭性的细胞内机制 扩散。我们还将在小鼠模型中检验补充传统的 用Pyk2/FAK阻滞剂治疗胶质母细胞瘤对肿瘤生长和复发的影响。 为了验证我们的假设，我们提出了以下具体目标： 具体目标#1：验证小胶质细胞激活胶质瘤迁移、侵袭和增殖的假说 细胞通过细胞内的Pyk2和FAK途径。 具体目的#2：研究替莫唑胺(TMZ)和Pyk2/FAK阻滞剂PF-2的联合作用。 关于肿瘤生长和动物死亡率的562271。 靶向#3：探讨曲美他滨联合PF-562271治疗脑胶质瘤的疗效 肿瘤切除后复发。 验证我们的假设将提供一个平台，以开发旨在消除 小胶质细胞成分对胶质瘤的生长和复发有促进作用，从而提高治疗效果。

Glioblastoma tumors carry an exceptionally poor prognosis with median survival of approximately one year following diagnosis. Treatment resistance and invasive nature of glioma tumors negates the effectiveness of current medical approaches. Microglia infiltrate most gliomas and release factors which influence tumor growth and invasion. It was shown that soluble factors, released by microglia activate migration, proliferation, and resistance to applied chemotherapy in cultured glioma cell lines. Previously we demonstrated that microglia promote dispersal of glioma cells through the Pyk2 signaling pathway. Our preliminary data show that pharmacological inhibition of Pyk2/FAK in glioma cells reduce proliferation and increase cytotoxic effect of temozolomide in the presence of microglia. We hypothesize that microglia release factors to promote migration, proliferation, chemotherapy resistance, and tumor recurrence through the Pyk2/FAK pathways. The use of Pyk2/FAK blockers will reduce the microglial effect on tumor growth, dispersal, recurrence, and resistance to therapy. Combinatorial therapies utilizing Pyk2/FAK inhibitors together with chemotherapeutic compounds have the potential to provide significant treatment benefits. In the present study, we will utilize resected human glioblastoma tissues and cell biology approaches to investigate the intracellular mechanisms exploited to promote microglia-activated glioma invasiveness and proliferation. We will also examine, in a murine model, the effectiveness of supplementing traditional chemotherapeutic glioblastoma treatment with a Pyk2/FAK blocker on tumor growth and recurrence. To test our hypothesis we propose the following specific aims: Specific Aim #1: To test the hypothesis that microglia activate migration, invasion and proliferation of glioma cells through Pyk2 and FAK intracellular pathways. Specific Aim #2: To investigate combined effect of temozolomide (TMZ) and the Pyk2/FAK blocker PF- 562271 on tumor growth and animal mortality. Specific aim #3: To investigate the effectiveness of combined treatment with TMZ and PF-562271 on glioma recurrence after tumor resection. Validation of our hypothesis will provide a platform for developing therapeutic strategies aimed at elimination of the microglial component on glioma growth and recurrence and, thereby, increasing treatment efficacy.