Targeting autophagy in the TME

靶向 TME 中的自噬

基本信息

批准号：
8495299
负责人：
HONG-GANG WANG
金额：
$ 18.77万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8495299
关键词：
Affect Animal Model Apoptosis Autophagocytosis Autophagosome Biochemical Biological Markers Biological Process Biology Blood Circulation Breast Cancer Cell Breeding Cancer cell line Cell Survival Cells Chloroquine Complex Detection Diagnosis Disease Dominant-Negative Mutation Evaluation Event Extravasation FDA approved Firefly Luciferases Flow Cytometry Future Genes Genetic Goals Human Hypoxia Imaging Techniques Interruption Investigation Light Microscopic Molecular Monitor Morbidity - disease rate Mus Neoplasm Circulating Cells Neoplasm Metastasis Nutrient Organ Oxygen Pharmaceutical Preparations Phenotype Primary Neoplasm Relative (related person)Resistance Site Testing Therapeutic Time Tumor Tissue Tumor-Associated Process Vorinostat Xenograft procedure abstracting cancer therapy chemotherapeutic agent cytotoxic deprivation design experience implantation implementation research improved in vivo lymphatic circulation malignant breast neoplasm mouse model neoplastic cell novel strategies outcome forecast research study response therapy resistant tool tumor tumor growth tumor microenvironment tumor xenograft vector

项目摘要

Project Summary/Abstract The major goal of this project is to test the idea that modulation of autophagy within the hypoxic tumor microenvironment (TME) can impact circulating tumor cell (CTC) survival, metastatic potential, and therapeutic response. The TME is a complex breeding ground for selection of aggressive tumor cells with an advantage of survival or metastatic potential and confers resistance to cytotoxic as well as targeted cancer therapy. The process of tumor metastasis consists of multiple steps, including tumor cell dissemination from the primary tumor site into the vasculature or lymphatic circulation (intravasation), survival during circulation, extravasation into the secondary site, and initiation and colonization at the target organ site. Tumor cells must successfully complete each step to give rise to clinically detectable metastatic disease. It is generally accepted that autophagy is essential for tumor cell survival under conditions of nutrient or oxygen deprivation, the hallmarks of the TME. However, the relative contribution of autophagy within the TME to the pro-survival, metastasis- prone, and therapy-resistant phenotypes of CTCs is similarly unknown. There is therefore a great opportunity to unravel this biology and shed light on better therapeutic designs as well as therapy monitoring. We hypothesize that hypoxia-induced autophagy within the TME contributes to CTC survival, tumor metastasis, and chemoresistance. To test this hypothesis, we propose the following Specific Aims: 1) To determine the importance of hypoxia-regulated autophagy in tumor growth and metastasis in xenograft mouse models; 2) To evaluate autophagy and apoptosis in xenograft tumors and CTCs; 3) To investigate the effect of hypoxia- induced autophagy on therapeutic response as detected and monitored in CTCs.

项目摘要/摘要该项目的主要目标是测试低氧肿瘤内自噬的观念微环境（TME）可以影响循环肿瘤细胞（CTC）存活，转移性和治疗性回复。 TME是选择侵袭性肿瘤细胞的复杂繁殖地，优势生存或转移潜力，并赋予对细胞毒性和靶向癌症治疗的抗性。这肿瘤转移的过程由多个步骤组成，包括肿瘤细胞从初级传播肿瘤部位进入脉管系统或淋巴循环（插入），循环期间的存活，渗出进入二级部位，以及目标器官位点的启动和定殖。肿瘤细胞必须成功完成每个步骤，引起临床可检测到的转移性疾病。普遍认为在养分或氧气剥夺条件下，自噬对于肿瘤细胞存活至关重要 TME。然而，TME内自噬对促生物，转移的相对贡献 CTC的俯卧和耐药表型同样未知。因此，有一个很好的机会揭示这种生物学并阐明更好的治疗设计以及治疗监测。我们假设缺氧引起的TME内自噬有助于CTC存活，肿瘤转移，和化学抗性。为了检验这一假设，我们提出以下特定目的：1）确定异种移植小鼠模型中缺氧调节的自噬在肿瘤生长和转移中的重要性； 2）到评估异种移植肿瘤和CTC中的自噬和凋亡； 3）研究缺氧的作用 - 在CTC中检测和监测的对治疗反应的自噬诱导。