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，癌症患者最初对血管生成抑制剂有反应，他们的肿瘤会引起逃避性抵抗。临床前和临床数据进一步表明，血管生成抑制是肿瘤发展到更严重恶性阶段的驱动力，反映在肿瘤侵袭和扩散到周围组织中。侵袭性肿瘤复发背后的分子和细胞事件尚不完全清楚，需要进一步的临床前研究来阐明这种适应性规避抵抗的机制，从而设计和测试基于机制的联合治疗的潜力，旨在阻止单一抗血管生成治疗的这种潜在后果。我们的初步数据显示，在抗vegf治疗后，肿瘤获得了一种新的表型，其特征是胶质瘤细胞迁移、浸润和聚集，远离原始肿瘤肿块。此外，我们观察到Tie2+单核细胞（TEMs）在经历细胞外基质重塑的肿瘤区域大量积累。胶质瘤细胞和tem共培养显示出体外迁移和侵袭能力增强。此外，我们还建立了一个新的生理相关的人类生物基质培养系统，以检测胶质瘤细胞在3D条件下与tem共培养时的侵袭性。我们还建立了一个转基因动物模型来明确确定基质在肿瘤侵袭中的作用。这些发现表明，抗vegf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，我们提出以下目标：具体目标1：确定抗vegf治疗对颅内异种移植物中宿主细胞浸润的影响。特异性目的2：分析抗vegf治疗难治性肿瘤中表达Tie2的单核细胞的表型和功能特征。特异性目的：体内研究tem在肿瘤抗血管生成治疗难治性中的作用。这项工作的重点是在抗vegf治疗的脑肿瘤中建立tem与肿瘤扩散之间的功能机制联系。由于抗vegf治疗的肿瘤复发具有侵袭性增高的特点，因此可能与肿瘤进展过程中基质细胞内在或治疗诱导的促侵袭因子表达有关，从而导致肿瘤扩散。由于肿瘤间质被认为是癌症治疗的新兴靶点，确定对间质细胞侵袭的严格控制将提供新的治疗途径。

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. PUBLIC HEALTH RELEVANCE: Anti-angiogenesis drugs are among the most promising agents to treat brain tumors; however, potent angiogenesis inhibition alters the natural history of tumors by increasing invasion and promoting tumor dispersal. We believe that interactions of glioma cells with monocyte-infiltrating tumors expressing a key cellular receptor termed Tie2 are the basis for the heightened invasiveness. Results obtained from this proposal should propel the development of new therapies combining the targeting of vascular structures in the tumor and the Tie2+ monocytes and, as a result, improve the effect of anti-angiogenesis therapies and the prognosis of malignant brain tumors.