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Molecular Mechanisms of Cachexia in Lung Cancer

肺癌恶病质的分子机制

基本信息

批准号：
8964195
负责人：
CARLO M CROCE
金额：
$ 42.91万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8964195
关键词：
Address Apoptosis Binding Blood Circulation Body Weight decreased Cachexia Cancer Etiology Cancer Patient Cell Death Cell surface Cells Cessation of life Characteristics Chromosome Mapping Critical Pathways Cytogenetics Cytoplasm Development Diagnosis Disease Down-Regulation Early Diagnosis Endosomes Environment Fatty acid glycerol esters Genes Genetic Engineering Genetic study Genome Goals Growth and Development function Homologous Gene Human Inflammation Inflammatory Interferons Interleukin-1 Interleukin-6 Knowledge Lung Lung Neoplasms Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of lung Malignant neoplasm of pancreas Malnutrition MicroRNAs Modeling Molecular Monitor Mus Muscle Muscle Cells Muscle Fibers Myoblasts Neoplasm Metastasis Oligonucleotides Outcome Pancreas Pathogenesis Pathway interactions Patients Pattern Play Pre-Clinical Model Precursor RNA Process Production Quality of life Receptor Signaling Research Personnel Role Secondary to Staging Starvation Syndrome TLR8 gene Techniques Therapeutic Therapeutic Intervention Toll-like receptors Translating Tumor Necrosis Factor-alpha Tumor Suppressor Genes Tumor-Derived Untranslated RNA Vesicle aptamer base cancer cachexia cancer cell circulating microRNA cohort cytokine extracellular human TLR8 protein human TNF protein improved in vivo innovative technologies lean body mass macrophage multidisciplinary nanoengineering neoplastic cell novel novel therapeutics nucleolin outcome forecast overexpression prognostic public health relevance response trafficking tumor wasting

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is a devastating disease that carries a poor prognosis. Despite the advent of early detection and targeted therapeutics, interventions that can improve outcome are still needed. Cachexia is a syndrome characterized by unintended weight loss resulting from a reduction in lean body mass and fat mass that accompanies the development and growth of malignant tumors. Cachexia is also associated with a significant decline in quality of life, poor response to therapies and reduced survival in lung cancer. Investigators have sought to identify the underlying molecular mechanisms for cachexia with the hopes of translating these findings into therapy; however, attempts at targeting inflammation as a means for reducing cachexia have been largely unsuccessful. Recently, we made the novel discovery that cancer cells secrete Extracellular Vesicles, EV, (microvesicles/exosomes) containing microRNAs that can fuse with cells in the microenvironment. We have also determined that this phenomenon extends to muscle. We have shown that microvesicle microRNAs, particularly miR-21, secreted by tumor cells are capable of inducing cell death in myoblasts by a TLR-8/7 dependent pathway thus leading to cachexia. We hypothesize that patients with lung cancer associated cachexia have a distinct pattern of microvesicle/exosome miRNA expression and that tumor associated vesicle miRNAs (Including miR-21) induce muscle cell death by a TLR- dependent mechanism leading to cachexia. In aim 1, we will demonstrate that EV microRNAs are dysregulated in murine models of cancer associated cachexia. We will also examine the role of TLR signaling as a central mechanism using genetically engineered murine models. We propose to quantify exosomal microRNAs in preclinical models. The quantification of the secreted microvesicles/exosomes by the tumor in lung tumor-carrying mice will be conducted in a multidisciplinary manner leveraging innovative technologies for capture and characterization. In aim 2, we will demonstrate a correlation between the development of cachexia in patients with lung cancer and their circulating levels of microvesicle/exosome miRNAs. We propose to examine circulating microRNAs in a cohort of patients with advanced stage lung cancer (N=200). Our goal will be to develop a signature for lung cancer associated cachexia that may be applied for prognostic and surveillance purposes during the course of therapy. In aim 3, we will demonstrate that targeting select microvesicle/exosome miRNAs in vivo using aptamers will reduce cachexia. We propose to inhibit processing of select miRNAs (miR-21) using aptamers in lung tumor bearing mice.