Role of TEMs in brain tumor dispersal

描述（由申请人提供）：治疗剂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，最初对血管生成抑制剂有反应的癌症患者的肿瘤引起了逃避性耐药性。临床前和临床数据进一步表明，血管生成抑制是肿瘤进展至更大恶性阶段的驱动力，反映在侵袭性增强和肿瘤扩散至周围组织中。基于侵袭的肿瘤复发的分子和细胞事件尚不完全清楚，应保证进一步的临床前研究，以阐明这种适应性逃避耐药的机制，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潜力。我们的初步数据显示，抗VEGF治疗后，肿瘤获得了一个新的表型，其特征是远离原始肿瘤块的胶质瘤细胞的迁移，浸润和聚集。此外，我们观察到Tie 2+单核细胞（TEM）在经历细胞外基质重塑的肿瘤区域中的显著积累。胶质瘤细胞和TEM的共培养物在体外显示出增加的迁移和侵袭能力。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，以检查在3D条件下与TEM共培养时胶质瘤细胞的侵袭。我们还建立了一个转基因动物模型，以明确确定间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引发和招募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VEGF治疗对颅内异种移植物中宿主细胞浸润的影响。具体目标2：分析抗VEGF治疗难治性肿瘤中Tie 2表达单核细胞的表型和功能特征。具体目标3：在体内检查TEM在肿瘤对抗血管生成治疗无效性中的作用。这项工作的重点是建立TEM和肿瘤扩散之间的功能机制联系，在脑肿瘤治疗抗VEGF疗法。因为用抗VEGF疗法治疗的肿瘤的复发的特征在于侵袭性增强，所以可能涉及在肿瘤进展期间基质细胞内在的或治疗诱导的促侵袭因子的表达，从而导致肿瘤扩散。鉴定基质细胞对侵袭的严格控制应该提供新的治疗途径，因为肿瘤基质被认为是癌症治疗的新兴靶点。 公共卫生相关性：抗血管生成药物是治疗脑肿瘤最有前途的药物之一;然而，有效的血管生成抑制通过增加侵袭和促进肿瘤扩散来改变肿瘤的自然史。我们相信，胶质瘤细胞与单核细胞浸润性肿瘤的相互作用，表达一种关键的细胞受体Tie 2是增强侵袭性的基础。从这一提议中获得的结果应该推动结合靶向肿瘤中的血管结构和Tie 2+单核细胞的新疗法的开发，并因此改善抗血管生成疗法的效果和恶性脑肿瘤的预后。

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.