Role of TEMs in brain tumor dispersal

描述(由申请人提供)：治疗药物抑制胶质瘤生长的能力受到耐药性发展的极大限制。目前，使用抗血管生成疗法的临床试验显示出令人鼓舞的结果。然而，临床实践表明，肿瘤患者最初对血管生成抑制剂有反应时，会产生一种逃避抵抗。临床前和临床数据进一步表明，血管生成抑制是肿瘤进展到更恶性阶段的驱动力，反映在肿瘤的高度侵袭和肿瘤向周围组织的扩散。侵袭性肿瘤复发的分子和细胞事件还不完全清楚，需要进一步的临床前研究来阐明这种适应性-回避耐药的机制，从而设计和测试旨在阻止单一抗血管生成治疗的这种潜在后果的基于机制的联合治疗的可能性。我们的初步数据显示，在抗血管内皮生长因子治疗后，肿瘤获得了一种新的表型，其特征是胶质瘤细胞在远离原始肿瘤块的地方迁移、渗透和聚集。此外，我们观察到在经历细胞外基质重塑的肿瘤区域，Tie2+单核细胞(TEM)显著积聚。胶质瘤细胞与TEM共培养显示体外迁移和侵袭能力增强。此外，我们还建立了一种新的与生理相关的人生物基质培养系统，以检测在3D条件下与TEM共培养时胶质瘤细胞的侵袭性。我们还建立了转基因动物模型，以明确地确定间质在肿瘤侵袭中的作用。这些发现表明，抗血管内皮生长因子治疗后的复发是由肿瘤启动和招募TEM的能力决定的。为了验证我们的假设并实现本项目的目标，我们提出了以下目标：具体目标1：确定抗血管内皮生长因子治疗对异种颅内移植瘤宿主细胞浸润的影响。特异性目的2：分析抗血管内皮生长因子治疗耐药肿瘤中表达Tie2的单核细胞的表型和功能特征。目的：在体内检测TEM在肿瘤抗血管生成治疗中的作用。这项工作的重点是在使用抗血管内皮生长因子治疗的脑肿瘤中建立TEMS和肿瘤扩散之间的功能机制联系。由于抗血管内皮生长因子治疗的肿瘤复发以高侵袭性为特征，可能与肿瘤进展过程中基质细胞固有的或治疗诱导的侵袭因子表达有关，从而导致肿瘤的扩散。随着肿瘤间质被认为是癌症治疗的新靶点，识别基质细胞对侵袭的严密控制应该会提供新的治疗途径。

DESCRIPTION (provided by applicant): The ability of therapeutic agents to inhibit glioma growth is drastically limited by the development of resistance. Currently, clinical trials using anti-angiogenesis therapies are showing encouraging results. However, clinical practice reveals that cancer patients initially responding to angiogenesis inhibitors their tumors elicit an evasive resistance. Pre-clinical and clinical data further implicate angiogenesis inhibition as a driving force in tumor progression to stages of greater malignancy, reflected in heightened invasion and tumor dispersal into surrounding tissue. The molecular and cellular events underlying the invasion-based tumor recurrence are incompletely understood, and further preclinical studies should be warranted to elucidate the mechanisms of this adaptive-evasive resistance, so as to design and test the potential of mechanism-based combination therapies aimed at impeding this insidious consequence of singular antiangiogenic therapy. Our preliminary data show that, following anti-VEGF treatment, the tumors acquired a new phenotype that was characterized by migration, infiltration and aggregations of glioma cells far from the original tumor mass. In addition, we observed a dramatic accumulation of Tie2+ monocytes (TEMs) in the tumor areas undergoing extracellular matrix remodeling. Co-cultures of glioma cells and TEMs showed increased migration and invasion capabilities in vitro. In addition we have set up a novel physiologically-relevant human biomatrix culture system to examine the invasion of glioma cells when co-cultured with TEMs in 3D conditions. We have also established a transgenic animal model to unequivocally determine the role of the stroma in tumor invasion. These findings suggest that recurrence after anti-VEGF treatment is determined by the ability of tumors to prime and recruit TEMs. To test our hypothesis and achieve the objectives of this project we propose the following Aims: Specific Aim 1: Determine the effects of anti-VEGF therapy on host cell infiltrates in intracranial xenografts. Specific Aim 2: Analyze the phenotype and functional characteristics of Tie2 expressing monocytes in tumors refractory to anti-VEGF therapies. Specific Aim3: Examine in vivo the role of TEMs in the tumor refractoriness to anti-angiogenesis treatment. This work is highly focused on establishing a functional mechanistic link between TEMs and tumor dispersal in brain tumors treated with anti-VEGF therapies. Because the recurrence of tumors treated with anti-VEGF therapies is characterized by heighten invasion, stroma cell-intrinsic or treatment-induced expression of pro-invasion factors during tumor progression causing tumor dispersal might be implicated. Identifying the tight control of invasion by stroma cells should provide new therapeutic avenues as tumor stroma is considered an emerging target for cancer therapy.