Role of TEMs in brain tumor dispersal

TEM 在脑肿瘤扩散中的作用

• 批准号: 8723904
• 负责人: Candelaria Gomez-Manzano
• 金额: $ 33.53万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723904
• 关键词: Angiogenesis Inhibition; Angiogenesis Inhibitors; Animal Model; Animals; Antibodies; Area; Blood Circulation; Blood Vessels; Brain; Brain Neoplasms; Cancer Patient; Cells; Characteristics; Chemicals; Clinical; Clinical Data; Clinical Trials; Coculture Techniques; Combined Modality Therapy; Data; Development; Engineering; Event; Exhibits; Extracellular Matrix; Glioblastoma; Glioma; Growth; Human; Implant; In Vitro; Infiltration; Laboratories; Link; Literature; Long-Term Survivors; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Methods; Modeling; Molecular; Mus; Natural History; Patients; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Recruitment Activity; Recurrence; Refractory; Reporting; Resistance; Resistance development; Role; Solutions; Staging; Structure; System; Testing; Therapeutic Agents; Tissues; Transgenic Animals; Tumor Cell Invasion; Tumor Stem Cells; VEGF Trap; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Work; Xenograft procedure; antiangiogenesis therapy; base; bevacizumab; cancer cell; cancer therapy; cell stroma; clinical practice; design; driving force; improved; in vivo; migration; monocyte; neuro-oncology; novel; novel therapeutics; outcome forecast; pre-clinical; preclinical study; public health relevance; receptor; response; therapeutic angiogenesis; three dimensional structure; tumor; tumor growth; tumor progression; uptake

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.

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Tie2+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Tie2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。

项目成果

Tie2/TEK modulates the interaction of glioma and brain tumor stem cells with endothelial cells and promotes an invasive phenotype.

Tie2/TEK 调节神经胶质瘤和脑肿瘤干细胞与内皮细胞的相互作用，并促进侵袭表型。

• DOI: 10.18632/oncotarget.101204
• 发表时间: 2010
• 期刊: Oncotarget
• 作者: Liu,Dan;Martin,Vanesa;Fueyo,Juan;Lee,Ok-Hee;Xu,Jing;Cortes-Santiago,Nahir;Alonso,MartaM;Aldape,Kenneth;Colman,Howard;Gomez-Manzano,Candelaria
• 通讯作者: Gomez-Manzano,Candelaria

Macrophage Ablation Reduces M2-Like Populations and Jeopardizes Tumor Growth in a MAFIA-Based Glioma Model.

在基于 MAFIA 的神经胶质瘤模型中，巨噬细胞消融可减少 M2 样细胞群并危及肿瘤生长。

• DOI: 10.1016/j.neo.2015.03.003
• 发表时间: 2015-04
• 期刊: NEOPLASIA
• 影响因子: 4.8
• 作者: Gabrusiewicz, Konrad;Hossain, Mohammad B.;Cortes-Santiago, Nahir;Fan, Xuejun;Kaminska, Bozena;Marini, Frank C.;Fueyo, Juan;Gomez-Manzano, Candelaria
• 通讯作者: Gomez-Manzano, Candelaria

Anti-vascular endothelial growth factor therapy-induced glioma invasion is associated with accumulation of Tie2-expressing monocytes.

• DOI: 10.18632/oncotarget.1893
• 发表时间: 2014-04-30
• 期刊: Oncotarget
• 作者: Gabrusiewicz K;Liu D;Cortes-Santiago N;Hossain MB;Conrad CA;Aldape KD;Fuller GN;Marini FC;Alonso MM;Idoate MA;Gilbert MR;Fueyo J;Gomez-Manzano C
• 通讯作者: Gomez-Manzano C

Selection of a Novel Aptamer Against Vitronectin Using Capillary Electrophoresis and Next Generation Sequencing.

使用毛细管电泳和下一代测序选择一种针对玻璃体素的新型适体。

• DOI: 10.1038/mtna.2016.91
• 发表时间: 2016-11-15
• 期刊: Molecular therapy. Nucleic acids