Targeting autophagy in the TME

靶向 TME 中的自噬

• 批准号: 8395589
• 负责人: HONG-GANG WANG
• 金额: $ 16.64万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8395589
• 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 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; 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 xenograft; vector

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Successful implementation of this research will not only offer a better understanding of the biological functions of hypoxia-induced autophagy within the TME in tumor cell survival, metastatic potential, and therapeutic resistance, but will also aid in the effort to develop an invaluable tool to monitor molecular events and biomarkers in CTCs for guiding diagnosis, prognosis and treatment of cancer.

描述（由申请人提供）：该项目的主要目标是测试以下观点：低氧肿瘤微环境（TME）内自噬的调节可以影响循环肿瘤细胞（CTC）生存，转移性潜力和治疗反应。 TME是选择具有生存或转移潜力的侵袭性肿瘤细胞的复杂繁殖地，并赋予了对细胞毒性和靶向癌症治疗的耐药性。肿瘤转移的过程由多个步骤组成，包括从原发性肿瘤部位传播到脉管系统或淋巴循环（静脉内），生存 在循环期间，渗出到次级部位，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，以引起临床可检测到的转移性疾病。人们普遍认为，在养分或氧气剥夺的条件下，自噬对于肿瘤细胞的存活至关重要，这是TME的标志。然而，TME内自噬对CTC的亲卵巢，易旋转和耐治疗表型的相对贡献也未知。因此，有一个很好的机会来揭示这种生物学，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内的自噬有助于CTC存活，肿瘤转移和化学抗性。为了检验这一假设，我们提出了以下特定目的：1）确定异种移植小鼠模型中缺氧调节自噬在肿瘤生长和转移中的重要性； 2）评估异种移植肿瘤和CTC中的自噬和凋亡； 3）研究缺氧诱导的自噬对CTC中检测和监测的治疗反应的影响。 公共卫生相关性：这项研究的成功实施不仅将更好地理解低氧诱导的肿瘤细胞存活中TME内自噬的生物学功能，而且还将有助于开发出无价的工具来监测CTC中的分子事件和生物标志物，以监测CTCS中的分子事件和生物标记，以监测CTCS的癌症治疗和癌症治疗。