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Autophagy as a microenvironmental regulator of tumorigenesis and resistance

自噬作为肿瘤发生和耐药性的微环境调节剂

基本信息

批准号：
9126463
负责人：
GABRIELE BERGERS
金额：
$ 42.22万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9126463
关键词：
Ablation Angiogenic Switch Antimalarials Attenuated Autophagocytosis Autophagosome Biological Blood Vessels Cancer Model Cancer Patient Cell Survival Cells Cellular Stress Clinical Oncology Complex Cues Data Development Endothelial Cells Exhibits Genetic Glioblastoma Glioma Growth Health Homeostasis Human Immune Inflammatory Inflammatory Response Islet Cell Tumor KDR gene Laboratories Learning Malignant Neoplasms Mediating Mediator of activation protein Mesenchymal Modeling Paracrine Communication Pathway interactions Pilot Projects Process Production Publishing Recording of previous events Recruitment Activity Relapse Resistance Role Stem cells Stress Testing Therapeutic Toxic effect Transgenic Organisms Translating Tumor Angiogenesis Tumor Cell Invasion Tumor Stem Cells Vascular Endothelial Growth Factors angiogenesis base bevacizumab cancer cell cancer therapy clinically significant cytokine fitness in vivo in vivo Model inhibition of autophagy inhibitor/antagonist insight interest killings meetings monocyte neoplastic cell neovascularization novel paracrine response therapy resistant tumor tumor initiation tumor microenvironment tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Autophagy is an evolutionarily conserved lysosomal degradation process crucial for adaptation to stress and for cellular homeostasis. To date, the rationale for targeting autophagy against cancer has been attributed to its cell-autonomous effects as a tumor cell survival pathway. In contrast, the role of autophagy in the development and function of the tumor microenvironment, a critical mediator of tumor initiation, progression and response to therapy, remains obscure. This project merges our expertise in autophagy and angiogenesis to define the functions of the autophagy pathway in the microenvironmental control of invasion and angiogenesis. We seek to answer two fundamental questions in the field. First, how does tumor cell autophagy generate a microenvironment conducive for survival and invasion? Second, is endothelial cell autophagy a prerequisite for the initiation of angiogenesis and during reneovascularization to escape therapeutic vascular growth restrictions imposed by anti-angiogenic therapy? Our preliminary studies implicate autophagy in the production of pro-migratory cytokines, thereby facilitating tumor cell invasion directly, or by activating monocytes via paracrine signaling cues. In addition, our pilot studies indicate that endothelial cell-targete autophagy deletion impairs neovascularization in vivo, thereby revealing a cell specific functional requirement for autophagy for angiogenesis. Based on these results, we will leverage powerful in vivo cancer models uniquely available in our laboratories to pursue two specific aims. In Aim 1, we will define the role of tumor cell autophagy in promoting glioblastoma multiforme (GBM) invasion and resistance to anti-angiogenic therapy. In Aim 2, we will determine the functions of endothelial cell autophagy during neovascularization and response to anti-angiogenic therapy. Overall, this proposal will define new interconnections between autophagy and the microenvironment that direct cancer cell invasion, angiogenesis and therapeutic resistance.

描述（由申请人提供）：自噬是一种进化上保守的溶酶体降解过程，对适应应激和细胞稳态至关重要。迄今为止，靶向自噬治疗癌症的基本原理归因于其作为肿瘤细胞生存途径的细胞自主作用。相比之下，自噬在肿瘤微环境的发展和功能中的作用（肿瘤发生、进展和对治疗的反应的关键介质）仍然不清楚。该项目结合了我们在自噬和血管生成方面的专业知识，以确定自噬途径在入侵和血管生成的微环境控制中的功能。我们试图回答这个领域的两个基本问题。首先，肿瘤细胞自噬如何产生有利于生存和侵袭的微环境？其次，内皮细胞自噬是血管生成和血管再生过程中避免抗血管生成治疗所施加的治疗性血管生长限制的先决条件吗？我们的初步研究表明自噬参与了促迁移细胞因子的产生，从而直接促进肿瘤细胞的侵袭，或者通过旁分泌信号信号激活单核细胞。此外，我们的前期研究表明，内皮细胞靶向的自噬缺失会损害体内新生血管，从而揭示了血管生成对自噬的细胞特异性功能需求。基于这些结果，我们将利用我们实验室独有的强大的体内癌症模型来追求两个特定的目标。在Aim 1中，我们将定义肿瘤细胞自噬在促进多形性胶质母细胞瘤（GBM）侵袭和抵抗抗血管生成治疗中的作用。在目的2中，我们将确定内皮细胞自噬在新生血管形成过程中的功能和对抗血管生成治疗的反应。总的来说，这一建议将定义自噬和微环境之间的新相互联系，从而指导癌细胞的侵袭、血管生成和治疗抵抗。