Promotion of angiogenesis in lung cancer by MIF

MIF促进肺癌血管生成

基本信息

批准号：
7847611
负责人：
Douglas Arenberg
金额：
$ 27.66万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-07-18 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7847611
关键词：
Accounting American Angiogenic Factor Angiogenic Switch Apoptosis Bone Marrow Bypass CXC Chemokines Cancer Etiology Cell Surface Receptors Cell surface Cells Cessation of life Cytoplasmic Protein Data Disease Environment Epithelial Excision Flow Cytometry Goals Human Investigation Journals Laboratories Lung Neoplasms Malignant - descriptor Malignant neoplasm of lung Mediating Molecular Target Mononuclear Myeloid Cells Nature Neoplasm Metastasis Pathology Pathway interactions Patients Peptides Phenotype Recurrence Regulation Role Signal Transduction Specimen Stromal Cells Surface Testing Transgenic Mice Tumor Angiogenesis United States Vascular Endothelial Growth Factors Work angiogenesis cytokine high risk improved invariant chain macrophage magnetic beads meetings mouse model promoter receptor response tumor tumor growth tumor progression

项目摘要

The goal of my laboratory is to understand mechanisms by which tumors interact with their microenvironment in such a way as to promote angiogenesis, metastasis, and contribute to the lethal nature of lung cancer. In our initial proposal we studied the promotion of angiogenesis in lung cancer by the cytokine MIF, and determined that tumors can create an angiogenic milieu by activating one of several different pathways. Our data show that MIF indudces angiogenesis indirectly by activating the expression of angiogenic promoters from infiltrating macrophages. Additionally, MIF may act by increasing proloiferation, and reducing apoptosis of the malignant cels themselves. The receptor through which this pro-tumor activity is mediated remains unclear, but may be CD74, a cell surface form of the invariant chain if the HLA class II peptide. We propose to extend observations by determining whether the MIF-CD74 axis is critical in promoting tumor angiogenesis, proliferation, and protection from apoptosis or some combination of these. We recently determined that CD74 was widely expressed in human lung cancer tumors, in both the malignant epithelial compartment as well as on stromal cells. Using flow cytometry on fresh tumor specimens, we showed that CD74 (normally a cytoplasmic protein, with a small proportion being expressed on the cell surface) was surface associated in tumors on both myeloid cells, as well as in specimens in which myeloid cells had been depleted with magnetic beads. The expression of CD74 in tumors was associated with increased levels of angiogenic CXC chemokines, and increased vascularity when compared to tumors where CD74 was not detected (American Journal of Pathology. 2009;174:638- 646). This amended proposal will test the hypothesis, that; MIF promotes tumor growth by inducing the expression of CXC chemokinedependent angiogenic activity, mediated by MIF signaling through the CD74 receptor. We propose to extend our observations made in human tumors and mouse models in the course of our original project by determining the molecular targets of MIF signaling in lung cancer. We will continue our previous studies of the MIF-dependent promotion of angiogenesis, by performing the following specific aims. Specific aim: a) Determine the role of CD74 in the promotion of lung tumor growth by MIF, and b) to determine the role myeloid cells in the MIF-CD74 axis in lung cancer.

我实验室的目标是了解肿瘤与其微环境相互作用的机制，从而促进血管生成、转移并导致肺癌的致死性。在我们最初的提案中，我们研究了细胞因子 MIF 对肺癌血管生成的促进作用，并确定肿瘤可以通过激活几种不同途径之一来创建血管生成环境。我们的数据表明，MIF 通过激活浸润巨噬细胞的血管生成启动子的表达来间接诱导血管生成。此外，MIF 可能通过增加恶性细胞本身的增殖和减少凋亡来发挥作用。介导这种促肿瘤活性的受体尚不清楚，但可能是 CD74，它是 HLA II 类肽的不变链的细胞表面形式。我们建议通过确定 MIF-CD74 轴是否对于促进肿瘤血管生成、增殖和防止细胞凋亡或这些的某些组合至关重要来扩展观察。我们最近确定 CD74 在人类肺癌肿瘤中、恶性上皮区室以及基质细胞中广泛表达。通过对新鲜肿瘤标本进行流式细胞术，我们发现 CD74（通常是一种细胞质蛋白，一小部分在细胞表面表达）与骨髓细胞肿瘤以及骨髓细胞已被切除的标本中的表面相关。已耗尽磁珠。与未检测到 CD74 的肿瘤相比，肿瘤中 CD74 的表达与血管生成 CXC 趋化因子水平增加以及血管分布增加相关（American Journal of Pathology.2009；174：638-646）。该修改后的提案将检验以下假设： MIF 通过诱导 CXC 趋化因子依赖性血管生成活性的表达来促进肿瘤生长，该活性由 MIF 信号通过 CD74 受体介导。我们建议通过确定肺癌中 MIF 信号传导的分子靶标来扩展我们在原始项目过程中在人类肿瘤和小鼠模型中所做的观察。我们将通过执行以下具体目标，继续之前关于 MIF 依赖性促进血管生成的研究。具体目标：a) 确定 CD74 在 MIF 促进肺癌生长中的作用，b) 确定骨髓细胞在肺癌中 MIF-CD74 轴中的作用。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multidisciplinary Evaluation of Patients With Suspected Lung Cancer.

疑似肺癌患者的多学科评估。

DOI：
10.1097/cpm.0b013e3181c849fe
发表时间：
2010
期刊：
Clinical pulmonary medicine
影响因子：
0
作者：
Bauman,Kristy;Arenberg,Douglas
通讯作者：
Arenberg,Douglas

The epidemiology of pain during the last 2 years of life.

DOI：
10.7326/0003-4819-153-9-201011020-00005
发表时间：
2010-11-02
期刊：
Annals of internal medicine
影响因子：
39.2
作者：
Smith AK;Cenzer IS;Knight SJ;Puntillo KA;Widera E;Williams BA;Boscardin WJ;Covinsky KE
通讯作者：
Covinsky KE

NaF18-PET/CT Imaging of Secondary Hyperparathyroidism.

继发性甲状旁腺功能亢进症的 NaF18-PET/CT 成像。

DOI：
10.1007/s13139-015-0319-3
发表时间：
2015
期刊：
Nuclear medicine and molecular imaging
影响因子：
1.3
作者：
Win,AungZaw;Aparici,CarinaMari
通讯作者：
Aparici,CarinaMari

A comparison of methods for measuring rectal HIV levels suggests that HIV DNA resides in cells other than CD4+ T cells, including myeloid cells.

对直肠 HIV 水平测量方法的比较表明，HIV DNA 存在于 CD4 T 细胞以外的细胞中，包括骨髓细胞。

DOI：
10.1097/qad.0000000000000166
发表时间：
2014
期刊：
AIDS (London, England)
影响因子：
0
作者：
Yukl,StevenA;Sinclair,Elizabeth;Somsouk,Ma;Hunt,PeterW;Epling,Lorrie;Killian,Maudi;Girling,Valerie;Li,Peilin;Havlir,DianeV;Deeks,StevenG;Wong,JosephK;Hatano,Hiroyu
通讯作者：
Hatano,Hiroyu

What are the sources of hydrogen peroxide production by heart mitochondria?