Exosomes in tumor cell-mesenchymal stromal cell interaction

肿瘤细胞-间充质基质细胞相互作用中的外泌体

基本信息

批准号：
10177876
负责人：
Yves A DeClerck
金额：
$ 43.39万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10177876
关键词：
Ablation Address Binding Proteins Biogenesis Biological Blood Bone Marrow Bone Marrow Cells Breast Cancer cell line CCL2 gene CRISPR/Cas technology CXCL12 gene Cell Communication Cell Line Cell Proliferation Cell Survival Cell surface Cells Collaborations Communication Data Disseminated Malignant Neoplasm Drug resistance Environment Failure Fibroblast Growth Factor Galectin 3 Genetic Goals Growth Factor Hematopoiesis Hematopoietic stem cells Home Homing IL8 gene Impairment In Vitro Inflammatory Integrins Interleukin 6 Receptor Interleukin-6 Intervention Knock-out Laboratories Malignant - descriptor Malignant Neoplasms Mediating Mesenchymal Cell Neoplasm Metastatic Neoplasm to the Bone Molecular Morbidity - disease rate Mus Neoplasm Metastasis Neural Crest Neuroblastoma Nonmetastatic Organ Osteoclasts Osteolytic Outcome Patients Pediatric Neoplasm Pharmacology Play Prevention Production Proteins Reaction Role Signal Transduction Site Solid Neoplasm Surface Testing Transcription Coactivator Tropism Tumor-Derived Universities Vascular Endothelial Cell Vesicle base bone cancer cell cancer prevention cancer type cell growth chemokine cytokine exosome extracellular vesicles galactose receptor in vivo inhibitor/antagonist insight interest knock-down malignant breast neoplasm mesenchymal stromal cell mortality neoplastic cell neuroblastoma cell novel prevent receptor tumor tumor microenvironment tumor progression tumorigenic uptake vesicular release

Ablation Address Binding Proteins Biogenesis Biological Blood Bone Marrow Bone Marrow Cells Breast Cancer cell line CCL2 gene CRISPR/Cas technology CXCL12 gene Cell Communication Cell Line Cell Proliferation Cell Survival Cell surface Cells Collaborations Communication Data Disseminated Malignant Neoplasm Drug resistance Environment Failure Fibroblast Growth Factor Galectin 3 Genetic Goals Growth Factor Hematopoiesis Hematopoietic stem cells Home Homing IL8 gene Impairment In Vitro Inflammatory Integrins Interleukin 6 Receptor Interleukin-6 Intervention Knock-out Laboratories Malignant - descriptor Malignant Neoplasms Mediating Mesenchymal Cell Neoplasm Metastatic Neoplasm to the Bone Molecular Morbidity - disease rate Mus Neoplasm Metastasis Neural Crest Neuroblastoma Nonmetastatic Organ Osteoclasts Osteolytic Outcome Patients Pediatric Neoplasm Pharmacology Play Prevention Production Proteins Reaction Role Signal Transduction Site Solid Neoplasm Surface Testing Transcription Coactivator Tropism Tumor-Derived Universities Vascular Endothelial Cell Vesicle base bone cancer cell cancer prevention cancer type cell growth chemokine cytokine exosome extracellular vesicles galactose receptor in vivo inhibitor/antagonist insight interest knock-down malignant breast neoplasm mesenchymal stromal cell mortality neoplastic cell neuroblastoma cell novel prevent receptor tumor tumor microenvironment tumor progression tumorigenic uptake vesicular release

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项目摘要

ABSTRACT The bone marrow (BM) is a heterogeneous organ with a central function in cancer progression and metastasis. It constitutes a niche for disseminated tumor cells, protecting them from therapy, promoting their dormancy and allowing them to metastasize to other organs. Cancer cells home to and hijack the BM niche converting it to a malignant niche favorable to tumor cell proliferation and survival. Thus, studying the cross-talk between tumor cells and the BM microenvironment is a subject of high interest. A major effort of our laboratory has been to study the communication between cancer cells and BM-derived mesenchymal stromal cells (BM-MSC) that form the BM-niche and that we have shown to contribute to a protumorigenic tumor microenvironment (TME). We focus on neuroblastoma (NB), a neural crest-derived tumor that is the second most common solid tumor in children, and that frequently and specifically metastasizes to the bone and BM and on tumor exosomes. These extracellular vesicles (EV) have emerged as a new and powerful mechanism of communication between tumor cells and their environment through their ability to convey multi-molecular biological messages of a much higher complexity than single growth factors. Preliminary data in this application demonstrate that NB cells release exosomes enriched in syntenin, ALIX, the tetraspanin CD-63 and Gal-3BP which are captured by BM- MSC and a pros-tumorigenic inflammatory reaction. Our overarching hypothesis is that as a result of their activity on MSC, NB-derived exosomes prime the BM niche, promoting the homing and survival of NB cells in the BM. We specifically hypothesize that syntenin plays a central role in their biogenesis and that Gal-3BP controls their uptake by interacting with a protein at the surface of BM-MSC. In a first aim we will determine the contribution of NB-derived exosomes to the pre-metastatic BM niche and the contribution of syntenin to their biogenesis, combining pharmacological and genetic (knock down and knock out) approaches in vitro in cultures of patient-derived MSC and in vivo in metastatic and non-metastatic NB cell lines. In aim 2, we will identify in BM-MSC the protein(s) interacting with Gal-3BP that contribute(s) to the uptake of exosomes in MSC, and in collaboration with Dr. David Lyden (Cornell University, NY), compare exosomes from NB and breast cancer cell lines that differ in BM tropism for their uptake by BM-MSC and BM hematopoietic stem cells (HSC) focusing on Gal-3BP and integrin in their uptake. These studies will provide novel insight into mechanisms by which exosomes are involved in the communication between tumor cells and the BM niche. It is anticipated that these studies will ultimately identify targets for intervention or prevention of cancer metastasis.

抽象的骨髓（BM）是一种异质器官，在癌症进展和转移中具有中心功能。它构成了散布肿瘤细胞的利基市场，可保护它们免受治疗，促进其休眠和允许他们转移到其他器官。癌细胞回家并劫持了BM的利基市场，将其转换为A 有利于肿瘤细胞增殖和存活的恶性生殖位。因此，研究肿瘤之间的串扰细胞和BM微环境是一个引起人们感兴趣的主题。我们实验室的重大努力是研究癌细胞与BM衍生的间充质基质细胞（BM-MSC）之间的通信形成BM-niche，我们已经证明有助于杂种肿瘤微环境（TME）。我们专注于神经母细胞瘤（NB），这是一种神经rest衍生的肿瘤，是第二个最常见的实体瘤儿童，经常，专门向骨骼和BM以及肿瘤外泌体转移。这些细胞外囊泡（EV）已成为一种新的，有力的沟通机制肿瘤细胞及其环境通过传达多种分子生物学信息的能力比单一生长因子更高的复杂性。本应用程序中的初步数据证明了NB细胞释放外泌体富含同步，ALIX，四叠蛋白CD-63和GAL-3BP，这些外泌体由BM-捕获 MSC和肿瘤炎症反应。我们的总体假设是，由于他们在MSC上的活性，NB来源的外泌体主要是BM利基市场，促进了NB的归巢和存活率 BM中的细胞。我们特别假设同步在其生物发生和该GAL-3BP通过与BM-MSC表面的蛋白质相互作用来控制其摄取。首先我们将确定NB衍生的外泌体对中性BM利基市场的贡献和贡献与其生物发生的同步，结合了药理学和遗传（敲低）在转移性和非转移性NB细胞中的患者衍生MSC和体内培养物中的体外方法线。在AIM 2中，我们将在BM-MSC中识别蛋白质与Gal-3bp相互作用的蛋白在MSC的外泌体的吸收，并与David Lyden博士（纽约州康奈尔大学）合作进行比较来自NB和乳腺癌细胞系的外泌体在BM Tropism中因BM-MSC和BM的吸收而有所不同造血干细胞（HSC）在摄取中关注GAL-3BP和整联蛋白。这些研究将提供对外泌体参与肿瘤细胞和 BM利基。预计这些研究最终将确定干预或预防的目标癌症转移。