Role of Bone Microenvironment in Tax Induced Malignancies

骨微环境在税收诱发的恶性肿瘤中的作用

基本信息

批准号：
7876678
负责人：
KATHERINE M WEILBAECHER
金额：
$ 36.03万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-21 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7876678
关键词：
Address Adult Animal Model Animals Apoptosis Biogenesis Biological Assay Biological Models Biology Bioluminescence Biostatistics Core Bone Diseases Bone Resorption Bone neoplasms Cancer Biology Carcinoma Cell Cycle Arrest Cells Cellular biology Characteristics Collaborations Complex Coupled Data Development Disease Endothelial Cells Evaluation Evolution Gene Targeting Human Hypercalcemia Hypercalcemia of Malignancy Image In Vitro Inflammatory Interferon Type II Life Ligands Lymphocyte Lymphocyte Activation Lymphoma Lymphoproliferative Disorders MDM2 gene Macrophage Inflammatory Protein-1 Macrophage Inflammatory Proteins Malignant - descriptor Malignant Bone Neoplasm Malignant Neoplasms Mediating Mediator of activation protein Metastatic Neoplasm to the Bone Modeling Molecular Multiple Myeloma Mus Mutant Strains Mice Nature Neoplasm Metastasis Oncogene Proteins Oncogenic Osteoblasts Osteoclasts Osteogenesis Osteolytic Pathogenesis Pathologic Pathway interactions Penetrance Play Principal Investigator Production Program Research Project Grants Publishing RNA helicase A Reaction Recruitment Activity Regulation Research Research Personnel Retroviridae Role Severity of illness Signal Transduction Small Inducible Cytokine A3 Suggestion T-Cell Lymphoma TNFSF11 gene TP53 gene Taxes Teleconferences Transgenic Mice Transgenic Organisms Translational Research Tumor Suppressor Proteins Tumor-Infiltrating Lymphocytes Viral Viral Oncogene Virus base bone bone imaging cancer complication cell type cytokine in vivo Model insight interest leukemia leukemia/lymphoma mouse model neoplastic cell neutrophil novel osteosarcoma parathyroid hormone-related protein programs receptor response therapy design tumor tumor growth tumorigenesis

项目摘要

In Project 4 of this PPG we seek to continue and expand the fundamental information gained from our highly interactive studies of HTLV-1, which causes an aggressive T-cell lymphoma initiated by the oncoprotein Tax. Our studies indicate that Tax-induced malignancies produce alterations in the tumor microenvironment that enhance tumor growth, bone destruction and severity of disease through the expression of bone-derived factors and cytokines that recruit host cells in the tumor microenvironment including osteoclasts and inflammatory cells. We developed animal models of Tax-induced malignancies and identified a variety of critical mediators of bone destruction and metastasis in the tumor microenvironment. During the past 4 years the Rosol and Weilbaecher labs developed their common interests in the pathogenesis of bone metastases and bone biology. These investigators join their expertise in the proposed Project 4 to better elucidate the molecular mechanisms of HTLV-1 Tax on skeletal metastases and humoral hypercalcemia of malignancy (HHM). In the proposed Project 4, we hypothesize that RANKL/RANK signaling is the critical common pathway by which Tax-induced factors alter the bone microenvironment to cause the bone destruction and paraneoplastic complications such as hypercalcemia. Based on our published studies and new data our highly interactive group seeks to identify mechanisms of Tax-induced alterations of the bone microenvironment that induce hypercalcemia and enhance tumor growth in bone. Therefore, we have focused our specific aims to: 1) Characterize the mechanism(s) by which Tax-induced tumor cells induce RANKL production and modulate of RANK signaling in osteolytic bone disease and humoral hypercalcemia of malignancy, 2) Define the molecular mechanisms by which tumor cells from Tax-induced malignancies alter normal osteoblast biology, 3) Define the molecular pathogenesis of a novel animal model of human osteosarcoma in Tax+Arf-/- mice. Thus, this evolution of Project 4 will address mechanisms of bone disease and metastasis and provide for rational design of interventions of life threatening complications of cancer in bone.

在该PPG的项目4中，我们寻求继续并扩大从高度中获得的基本信息 HTLV-1的互动研究，该研究导致癌蛋白税引发的侵袭性T细胞淋巴瘤。我们的研究表明，税收引起的恶性肿瘤会在肿瘤微环境中发生改变通过骨的表达来增强肿瘤的生长，骨骼破坏和疾病严重程度在肿瘤微环境中募集宿主细胞在内的因素和细胞因子，包括破骨细胞和炎性细胞。我们开发了税收引起的恶性肿瘤的动物模型，并确定了各种各样的动物模型肿瘤微环境中骨破坏和转移的关键介体。在过去的四年中罗索尔和威尔巴切尔实验室在骨转移的发病机理中发展了他们的共同利益和骨生物学。这些调查人员加入了拟议项目4的专业知识，以更好地阐明 HTLV-1对骨骼转移和体液高钙血症的分子机制（HHM）。在拟议的项目4中，我们假设RANKL/等级信号是关键的常见税收引起的因素改变骨微环境会导致骨骼破坏和副塑性并发症，例如高钙血症。根据我们已发表的研究和新数据我们高度互动群体试图确定税收诱导的骨骼改变的机制诱导高钙血症并增强骨骼肿瘤生长的微环境。因此，我们有聚焦我们的特定目的是：1）表征税收诱导的肿瘤细胞的机制 RANKL的产生和骨质骨骼疾病和体液高钙血症中等级信号传导的调节恶性肿瘤，2）定义分子机制，该机制通过税收引起的恶性肿瘤肿瘤细胞改变正常成骨细胞生物学，3）定义人类新型动物模型的分子发病机理税收+ARF - / - 小鼠中的骨肉瘤。因此，项目4的这种演变将解决骨病的机制和转移，并为癌症威胁生命并发症的干预措施提供合理的设计骨。