Identification of key tumor cell-released factors that induce cachexia

诱导恶病质的关键肿瘤细胞释放因子的鉴定

• 批准号: 9095239
• 负责人: YI-PING LI
• 金额: $ 32.3万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9095239
• 关键词: Affect; Agonist; Amino Acids; Anorexia; Attenuated; Autophagocytosis; Baculoviruses; Binding; Biological Assay; Body Weight decreased; CCAAT-Enhancer-Binding Proteins; Cachexia; Cancer Patient; Catabolism; Cause of Death; Cell Culture Techniques; Cell membrane; Cells; Clinical; Clinical Trials; Colorectal Cancer; Complex; Data; Dependence; Development; Disease; Endotoxins; Etiology; Extracellular Space; FDA approved; Fatty acid glycerol esters; Genes; Health; Heat shock proteins; Human; Immune; In Vitro; Indium; Inflammation; Inflammatory Response; Insulin Resistance; Ion Exchange; Knockout Mice; Left; Length; Life; Ligands; Lysosomes; MAP Kinase Gene; MAPK14 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Metabolic syndrome; Modeling; Molecular; Molecular Chaperones; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Proteins; Muscular Atrophy; Neoplasm Metastasis; Pathway interactions; Patients; Peptide Signal Sequences; Pharmaceutical Preparations; Play; Protein Biosynthesis; Protein Secretion; Proteins; Proteolysis; RNA Interference; Reagent; Recombinants; Role; Serum; Signal Pathway; Signal Transduction; Skeletal Muscle; Stimulus; System; TLR4 gene; Testing; Ubiquitin; Up-Regulation; Wasting Syndrome; base; cancer cachexia; cancer cell; design; exosome; extracellular; gain of function; genetic manipulation; genetic regulatory protein; in vitro activity; in vivo; inhibitor/antagonist; mortality; mouse model; multicatalytic endopeptidase complex; muscle form; neoplastic cell; neutralizing antibody; novel; promoter; protein degradation; protein folding; receptor; release factor; success; transcription factor; tumor

DESCRIPTION (provided by applicant): Cachexia, a wasting disease characterized by progressive loss of muscle with or without loss of fat mass, is frequently associated with cancer and is estimated to be the immediate cause of death in 20% to 40% of cancer patients. The prominent clinical feature of cachexia is weight loss, along with anorexia, inflammation, insulin resistance, and increased muscle protein breakdown. However, due to the poor understanding of its etiology there is currently no FDA-approved treatment for cancer-induced cachexia. Based on existing data, we postulate that fast growing tumors sustain high-level protein synthesis by releasing factors to extract amino acids from skeletal muscle via stimulating proteolysis, which is mediated by the systems that govern cellular protein degradation. However, the identities of the key tumor cell-release factors that induce the catabolic actions remain elusive. In preliminary studies, we found that a number of cachectic tumor cells constitutively release specific heat shock proteins (HSPs), which appear to be critical agents in tumor-induced cachexia. Traditionally, HSPs are primarily known as intracellular molecular chaperones for protein folding, assembly, and translocation, thus making them cytoprotective. Recently, HSPs have been shown being released by certain cells, including tumor cells, into the extracellular space where they play a major role in intercellular crosstalk. Tumor cell-released HSPs have been shown to elicit inflammatory responses via immune cells and promote metastasis. Importantly, high serum level of HSP associates with the high mortality in patients with colorectal and lung cancer, of which cachexia is often the immediate cause of death. However, the effects of extracellular HSPs on muscle cells are unknown. Preliminary data suggest that tumor cell- released HSPs are crucial for tumor-induced muscle catabolism by acting directly on muscle cells to activate the cellular protein degradation systems. We propose to evaluate the role of tumor-released HSPs in the development of cachexia, utilizing cellular and molecular approaches, in cell culture and mouse models of cancer cachexia. Three specific aims will be pursued: 1) to evaluate the contribution of tumor cell-released HSPs to cachexia; 2) to elucidate the signaling mechanism through which extracellular HSPs induce muscle catabolism; and 3) to determine the mechanism of constitutive release of HSPs by tumor cells. Success of the current project would establish a new paradigm for the etiology and treatment of cancer cachexia. Despite the fact that cachexia affects about 50% of cancer patients, it is essentially left untreated. By understanding the role of extracellular HSPs in cancer cachexia through the proposed studies above, treatment of cancer cachexia in humans could be tested in the short-term by utilizing reagents that have already been approved by the FDA for human use or clinical trials that inhibit HSPs, their membrane receptors and intracellular signaling pathways, or their release from tumor cells.

描述（由申请人提供）：恶病质是一种消耗性疾病，其特征是肌肉的进行性损失，伴有或不伴有脂肪量的损失，通常与癌症相关，估计是20%至40%癌症患者死亡的直接原因。恶病质的主要临床特征是体重减轻，同时伴有厌食症、炎症、胰岛素抵抗和肌肉蛋白分解增加。然而，由于对其病因了解不足，目前还没有fda批准的治疗癌症引起的恶病质的方法。基于现有的数据，我们假设快速生长的肿瘤通过释放因子，通过刺激蛋白质水解从骨骼肌中提取氨基酸，从而维持高水平的蛋白质合成