Image-Based Phenotyping of Hepatocellular Carcinoma Cell Survival Under Ischemic Stress: Toward Metabolic Imaging of Cancer Dormancy Using Hyperpolarized Carbon-13 Technology

基于图像的缺血应激下肝细胞癌细胞存活表型：使用超极化碳 13 技术实现癌症休眠的代谢成像

• 批准号: 9150682
• 负责人: Terence P Gade
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150682
• 关键词: 2,4-Dinitrophenol; Acetates; Acids; Animal Model; Apoptosis; Arterial Embolization; Autophagocytosis; Biological Models; Biology; Blood Vessels; Cancer Survivor; Carbamyl Phosphate; Carbohydrates; Carbon; Carbon Dioxide; Cell Survival; Cells; Chemoembolization; Clinical; Dependence; Detection; Development; Disease; Environment; Enzymes; Epigenetic Process; Extensive Necrosis; Fingerprint; Fructose; Fumarates; Glucose; Glutamates; Glutamine; Growth; Guidelines; Health; Histology; Histopathology; Hypoxia Inducible Factor; Image; Imaging Techniques; Imaging technology; In Vitro; Ischemia; Label; Lesion; Leucine; Ligase; Lipids; Malates; Malignant Epithelial Cell; Malignant Neoplasms; Measurable; Measures; Metabolic; Metabolic stress; Metabolism; Modeling; NMR Spectroscopy; Necrosis; Non-Invasive Cancer Detection; Nuclear; Nutrient; Palmitates; Pathology; Patients; Phenotype; Primary carcinoma of the liver cells; Proliferating; Protein Biosynthesis; Proteins; Proteomics; Pyruvate; Rattus; Recurrence; Resources; Signal Transduction; Solid Neoplasm; Stress; Technology; Therapeutic; Therapeutic Embolization; Time; Tissues; Translating; Translations; Tumor Cell Necrosis; Work; alpha ketoglutarate; base; biological adaptation to stress; cancer cell; cancer imaging; carbohydrate metabolism; epigenetic profiling; follow-up; in vivo; indexing; lens; lipid biosynthesis; lipid metabolism; liver transplantation; metabolic abnormality assessment; metabolomics; neoplastic cell; novel; nutrient deprivation; pre-clinical; programs; protein metabolism; research study; response; spectroscopic imaging; targeted delivery; tumor; tumor metabolism

 DESCRIPTION (provided by applicant): Established guidelines for assessing response of solid tumors to therapy are based on conventional imaging indices, such as tumor size and vascularity, and were intended to facilitate a uniform assessment of response to systemically administered chemotherapeutics that target proliferating cells in a well-perfused microenvironment. An emerging imaging phenotype of tumor recurrence indicates that a complete radiographic response may be followed by variable periods of latency without perceptible growth in poorly perfused microenvironments. This imaging phenotype highlights the capability of cancer cells to adapt their growth program to their microenvironment and effect tumor dormancy. The development of functional measures of this altered tumor metabolism is critical to effective preclinical and clinical imaging of response. Trans-arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) provides a compelling clinical correlate to this imaging deficiency. TACE exploits the vascular biology of HCC to deprive tumors of nutrients, leading to necrosis; however, only 44% of large treated lesions demonstrate extensive necrosis on pathology, underscoring the adaptive response of HCC cells to nutrient deprivation. This adaptive response is reflected by the presence of viable tumor cells adjacent to regions of necrosis on histopathology, and is consistent with the rapid recurrence following a period of latency that is often discovered on follow-up imaging. Thus, TACE provides a useful model for identifying the mechanisms mobilized by cancer cells to survive severe ischemia. In preliminary studies, we have demonstrated that TACE-like severe ischemia induces quiescence in surviving cells and that these cells activate a metabolic stress response (MSR) including hypoxia-inducible factors, the unfolded protein response and autophagy, which reprogram metabolism to enable survival under ischemic conditions. The recent development of Dynamic Hyperpolarized Carbon-13 Nuclear Magnetic Resonance spectroscopy and spectroscopic imaging (DNP-13C-NMRS) has yielded promising results in studies of metabolism in hepatocellular disease. This technology represents a unique resource to translate advances in our understanding of the MSR into a non-invasive, clinically applicable imaging paradigm to identify dormant cancer cells surviving ischemia. The conventional post-TACE imaging phenotype of sustained survival without proliferation under metabolic stress will be examined using targeted metabolomics, proteomic and epigenetic profiling of HCC cells to develop a DNP-13C-NMRS based imaging approach. The primary objectives of this application are to: a) characterize the nutrient microenvironment as well as the epigenetic and proteomic alterations underlying MSR-induced metabolic adaptation in cells surviving ischemic stress, b) develop a DNP- 13C-NMRS based metabolic imaging approach to enable the non-invasive detection of cells surviving ischemic stress in vitro, and c) translate this approach to characterize cells surviving trans-arterial embolization in vivo.

 描述（由适用提供）：评估实体瘤对治疗反应的既定指南基于常规成像指数，例如肿瘤大小和血管性，旨在促进对系统施用的化学治疗剂的均匀评估，这些反应旨在靶向在良好的微环境中靶向靶向细胞的靶向。肿瘤复发的新兴成像表型表明，完整的放射线照相响应之后可能是可变的潜伏期，而灌注不良的微环境中的延迟，而无需可见的生长。这种成像表型突出了癌细胞使其生长程序适应其微环境和影响肿瘤休眠的能力。这种改变的肿瘤代谢的功能度量的发展对于有效的临床前和临床反应成像至关重要。用于治疗肝细胞癌（HCC）治疗的跨性别化学栓塞（TACE）提供了与这种成像缺乏的引人注目的临床相关性。 TACE探讨了HCC的血管生物学，以剥夺肿瘤的营养，导致坏死。但是，只有44％的大型治疗病变表现出病理学的广泛坏死，强调了HCC细胞对营养缺乏的适应性反应。这种自适应反应反映出与组织病理学上坏死区相邻的可行肿瘤细胞的存在，并且与经常在后续成像中经常发现的潜伏期后的快速复发一致。这是TACE提供了一个有用的模型，用于识别由癌细胞动员严重缺血的机制。在初步研究中，我们已经证明，TACE样严重的缺血会影响存活细胞的静止，并且这些细胞激活了包括缺氧诱导因子，未折叠的蛋白质反应和自噬的代谢应激反应（MSR），这些反应和自噬，这些反应代谢可在缺血性条件下启用生存。动态超极化碳13核磁共振光谱和光谱成像（DNP-13C-NMR）的最新发展在肝细胞质疾病中代谢的研究中产生了希望的结果。这项技术代表了一种独特的资源，可以将我们对MSR理解的进步转化为一种无创，临床适用的成像范式，以鉴定持续性缺血的休眠性癌细胞。在代谢压力下，将使用靶向代谢组学，HCC细胞的蛋白质组学和表观遗传分析来检查持续生存的常规后传播成像表型，以开发基于DNP-13C-NMRS的成像方法。该应用的主要目标是：a）表征营养微环境以及表观遗传学和蛋白质组学改变，在存活的缺血压力的细胞中，MSR诱导的代谢适应性下的代谢适应性，b）开发DNP-13C-NMR基于基于非融合的反应且CREMATION INSCHECTION INSCHECTION INSCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION INSCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION ISCHECTION ANDECTOR STERICTION，并将其列为C）。在体内存活的跨动力栓塞。