Roles of Glycoconjugates and Redox Signaling in Tumor Biology

糖缀合物和氧化还原信号在肿瘤生物学中的作用

基本信息

批准号：
9780179
负责人：
david d roberts
金额：
$ 15.71万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9780179
关键词：
ADAMTS1 gene Acute Address Adverse effects Affect Affinity Anabolism Angiogenesis Inhibitors Animal Model Arachidonic Acids Binding Biological Biological Markers Biological Process CD44 Antigens CD44 gene CD47 gene Cancer Patient Cancer cell line Carbon Monoxide Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Catabolism Cell Adhesion Molecules Cell Surface Receptors Cell surface Cells Chemopreventive Agent Chronic Disease Clinical Trials Communication Development Diagnostic Distant Eicosanoids Elements Enzymes Etiology Exhibits Extracellular Matrix FDA approved Family Glycoconjugates Glycolipids Glycoproteins Hemostatic function Heparan Sulfate Proteoglycan Homeostasis Hyaluronan Hydrogen Sulfide Immunologic Surveillance Inflammation Inflammatory Injury Integrins Knockout Mice Lead Ligands Lipids Malignant Neoplasms Marfan Syndrome Mediating Mediator of activation protein Metabolic Pathway Mitogen-Activated Protein Kinases Molecular Mus Mutant Strains Mice Neoplasm Metastasis Nitrogen Organ Organism Oxidation-Reduction Oxygen Pathogenesis Pathologic Neovascularization Pathology Pathway interactions Patients Pharmaceutical Preparations Play Polysaccharides Polyunsaturated Fatty Acids Post-Translational Protein Processing Process Production Proteins Proteoglycan Receptor Signaling Role Signal Pathway Signal Transduction Signaling Molecule Signaling Protein Splenocyte Structure Superoxides T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Uses Thrombospondin 1 Thrombospondins Thymus Gland Transducers Transgenic Model Treatment Efficacy Tumor Angiogenesis Tumor Biology Tumor Tissue Vascular Diseases Wild Type Mouse angiogenesis autocrine blood pressure regulation cancer cell cancer prevention cancer therapy carcinogenesis cell type eicosanoid metabolism glycosylation improved inhibitor/antagonist mechanical properties neoplastic cell neovascularization novel therapeutics prevent receptor response response to injury small molecule therapeutic target thymocyte treatment strategy tumor microenvironment tumor progression

项目摘要

Cells in multicellular organisms communicate extensively with neighboring cells and distant organs using a variety of secreted proteins and small molecules. Cells also reside in a structural extracellular matrix (ECM), and changes in its composition, mechanical properties, and post-translational modifications provide additional layers of communication. This Forum addresses emerging mechanisms by which redox signaling controls and is controlled by changes in the ECM, focusing on the roles of matricellular proteins. These proteins engage specific cell surface signaling receptors, integrins, and proteoglycans to regulate the biosynthesis and catabolism of redox signaling molecules and the activation of their signal transducers. These signaling pathways, in turn, regulate the composition of ECM and its function. Covalent post-translational modifications of ECM by redox molecules further regulate its structure and function. Recent studies of acute injuries and chronic disease have identified important pathophysiological roles for this cross-talk and new therapeutic opportunities. In contrast to structural elements of the extracellular matrix, matricellular proteins appear transiently during development and injury responses, but their sustained expression can contribute to chronic disease. Through interactions with other matrix components and specific cell surface receptors matricellular proteins regulate multiple signaling pathways, including those mediated by reactive oxygen and nitrogen species and H2S. Dysregulation of matricellular proteins contributes to the pathogenesis of vascular diseases and cancer. Defining the molecular mechanisms and receptors involved is revealing new therapeutic opportunities. Recent advances have revealed that thrombospondin-1 regulates NO, H2S, and superoxide production and signaling in several cell types. The thrombospondin-1 receptor CD47 plays a central role in inhibition of NO signaling, but other thrombospondin-1 receptors also modulate redox signaling. The matricellular protein CCN1 engages some of the same receptors to regulate redox signaling, and ADAMTS1 regulates NO signaling in Marfan syndrome. In addition to mediating matricellular protein signaling, redox signaling is emerging as an important pathway that controls the expression of several matricellular proteins. Redox signaling remains unexplored for many matricellular proteins. Their interactions with multiple cellular receptors remains an obstacle to defining signaling mechanisms, but improved transgenic models could overcome this barrier. FUTURE DIRECTIONS: Therapeutics targeting the TSP1 receptor CD47 may have beneficial effects for treating cardiovascular disease and cancer and have recently entered clinical trials. Biomarkers are needed to assess their effects on redox signaling in patients and to evaluate how these contribute to their therapeutic efficacy and potential side effects. The metabolism of arachidonic acid and other polyunsaturated fatty acids produces eicosanoids, a family of biologically active lipids that are implicated in homeostasis and in several pathologies that involve inflammation. Inflammatory processes mediated by eicosanoids promote carcinogenesis by exerting direct effects on cancer cells and by affecting the tumor microenvironment. Therefore, understanding how eicosanoids mediate cancer progression may lead to better approaches and chemopreventive strategies for the treatment of cancer. The matricellular protein thrombospondin-1 is involved in processes that profoundly regulate inflammatory pathways that contribute to carcinogenesis and metastatic spread. This review focuses on interactions of thrombospondin-1 and eicosanoids in the microenvironment that promote carcinogenesis and how the microenvironment can be targeted for cancer prevention to increase curative responses of cancer patients.

多细胞生物中的细胞使用各种分泌的蛋白质和小分子与邻近细胞和远处器官进行广泛的交流。细胞还存在于结构细胞外基质 (ECM) 中，其组成、机械性能和翻译后修饰的变化提供了额外的通讯层。本论坛讨论氧化还原信号控制 ECM 变化以及受 ECM 变化控制的新兴机制，重点关注基质细胞蛋白的作用。这些蛋白质与特定的细胞表面信号受体、整合素和蛋白聚糖结合，调节氧化还原信号分子的生物合成和分解代谢及其信号转导器的激活。这些信号通路反过来调节 ECM 的组成及其功能。氧化还原分子对 ECM 的共价翻译后修饰进一步调节其结构和功能。最近对急性损伤和慢性疾病的研究已经确定了这种串扰的重要病理生理学作用和新的治疗机会。与细胞外基质的结构元件相反，基质细胞蛋白在发育和损伤反应期间短暂出现，但它们的持续表达可能导致慢性疾病。通过与其他基质成分和特定细胞表面受体的相互作用，基质细胞蛋白调节多种信号传导途径，包括由活性氧、氮物质和 H2S 介导的信号传导途径。基质细胞蛋白的失调导致血管疾病和癌症的发病机制。定义所涉及的分子机制和受体正在揭示新的治疗机会。最近的进展表明，血小板反应蛋白-1 可调节多种细胞类型中 NO、H2S 和超氧化物的产生和信号传导。血小板反应蛋白-1 受体 CD47 在抑制 NO 信号传导中发挥核心作用，但其他血小板反应蛋白-1 受体也调节氧化还原信号传导。基质细胞蛋白 CCN1 与一些相同的受体结合来调节氧化还原信号传导，而 ADAMTS1 则调节马凡综合征中的 NO 信号传导。除了介导基质细胞蛋白信号传导之外，氧化还原信号传导正在成为控制多种基质细胞蛋白表达的重要途径。许多基质细胞蛋白的氧化还原信号传导仍未被探索。它们与多种细胞受体的相互作用仍然是定义信号传导机制的障碍，但改进的转基因模型可以克服这一障碍。未来方向：针对 TSP1 受体 CD47 的治疗可能对治疗心血管疾病和癌症具有有益作用，并且最近已进入临床试验。需要生物标志物来评估它们对患者氧化还原信号传导的影响，并评估它们如何影响其治疗效果和潜在副作用。花生四烯酸和其他多不饱和脂肪酸的代谢产生类二十烷酸，这是一类具有生物活性的脂质，与体内平衡和涉及炎症的多种病理有关。类二十烷酸介导的炎症过程通过对癌细胞产生直接影响并影响肿瘤微环境来促进癌变。因此，了解类二十烷酸如何介导癌症进展可能会导致更好的癌症治疗方法和化学预防策略。基质细胞蛋白血小板反应蛋白-1 参与深刻调节炎症途径的过程，从而促进癌发生和转移扩散。本综述重点关注促进癌发生的微环境中血小板反应蛋白-1 和类二十烷酸的相互作用，以及如何以微环境为目标进行癌症预防，以提高癌症患者的治疗反应。