Potential Role of Fetal Stem Cells in Lung Tumor Development

胎儿干细胞在肺肿瘤发展中的潜在作用

基本信息

批准号：
7576739
负责人：
JANET A SAWICKI
金额：
$ 18.56万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576739
关键词：
Adjuvant Affect Age Antibodies Biological Assay Birth Blood Blood Circulation Breeding Cancer Patient Cardiovascular system Cell Therapy Cell fusion Cell physiology Cells Cessation of life Characteristics Cyprinus carpio DNA DNA Probes Detection Development Disease Epithelial Epithelial Cells Erythroblasts Event FVB Mouse Female Firefly Luciferases Fluorescent in Situ Hybridization Frequencies Green Fluorescent Proteins Growth and Development function Hand Hematopoietic Hematopoietic stem cells Hepatocyte Hospitals Image Incidence Injection of therapeutic agent Injury Knowledge Lead Left Leukocytes Luciferases Lung Lung Neoplasms Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Microchimerism Modeling Monitor Mothers Mus Normal tissue morphology Optics Partner in relationship Pathology Patients Physicians Play Positioning Attribute Predisposition Pregnancy Prostate Reporter Research Research Personnel Role Sampling Specimen Stem cells Stromal Cells Structure of parenchyma of lung Surgeon Testing Therapeutic Time Tissues Transgenes Transgenic Mice Transgenic Organisms Ursidae Family Woman Work X Chromosome Y Chromosome base boys cell type clinical application experience fetal fetal stem cell fetus cell fish Carp girls lung tumorigenesis male mouse model neoplastic cell novel parity pup research study stem tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Fetal cells enter the maternal circulatory system during pregnancy and can persist in low numbers in the blood and tissues for years, even decades. This phenomenon is referred to as fetal microchimerism. Most fetal cells that enter the maternal circulation during pregnancy are of hematopoietic origin, such as nucleated red blood cells, lymphocytes, or hematopoietic stem cells. Remarkably, it has been shown that microchimeric fetal cells can express epithelial, leukocyte, or hepatocyte markers in maternal tissue specimens from women afflicted by a variety of diseases long after pregnancy. This observation suggests that fetal cells may respond to maternal injury by differentiating into multiple cell types, a defining characteristic of stem cells. In recent work, we and others have developed a mouse model to study fetal microchimerism and have discovered that the frequency of fetal cells in the lungs is significantly higher than in other tissues. In a remarkable discovery, we have observed large numbers of fetal cells associated with a lung tumor that developed in a mouse following pregnancy. Our observations on fetal microchimerism in the lung have led us to hypothesize that fetal stem cells harbored in the lungs of women following pregnancy influence the development of lung cancer in women, either by increasing susceptibility of women for lung cancer, or just the opposite, by suppressing the growth and development of lung tumors. To test this hypothesis, we will tag murine fetal cells with two transgenes, one that genetically initiates lung tumors and another that encodes luciferase. We will optically image female mice bearing these cells to screen for bioluminescing lung tumors. We will also use mouse models to explore the relationship between the number of pregnancies and the incidence of lung cancer. In another study, we will screen DNA extracted from lung tumors from women who have given birth to a baby boy or boys for the presence of the Y chromosome. Knowledge gained from this study may lead to the development of new therapies for lung cancer based on the role that fetal cells may play in lung tumorigenesis. In particular, if fetal cells contribute to tumor development, one can envision treating women lung cancer patients with adjuvant therapeutics that effectively target fetally-derived cells, thus sparing healthy tissues. If on the other hand, we discover that fetal cells function to suppress lung tumor growth, the finding could be the basis for development of a new cell therapy. Public Health Relevance: The purpose of this study is to test the hypothesis that fetal stem cells that remain in the lungs of women long after they have been pregnant can influence the development of lung cancer in women, either by increasing susceptibility of women for lung cancer, or just the opposite, by suppressing the growth and development of lung tumors. In considering possible clinical applications stemming from this study, if we find that fetal cells contribute to the development of lung tumors, this knowledge would open the door for the development of new genetically-based therapies for lung cancer that would target the death of fetally-derived tumor cells and leave healthy maternal lung tissue unharmed. If, on the other hand, we find evidence that fetal cells function to keep lung tumor growth in check in women, our findings may lead to a novel cell therapy for the treatment of lung cancer.

描述（由申请人提供）：胎儿细胞在怀孕期间进入母体循环系统，并且可以在血液和组织中以较低的数量持续数年，甚至数十年。这种现象称为胎儿微嵌合现象。大多数在怀孕期间进入母体循环的胎儿细胞都是造血来源的，例如有核红细胞、淋巴细胞或造血干细胞。值得注意的是，已经表明，微嵌合胎儿细胞可以在怀孕后很长时间内患有多种疾病的妇女的母体组织样本中表达上皮细胞、白细胞或肝细胞标记物。这一观察结果表明，胎儿细胞可能通过分化成多种细胞类型来应对母体损伤，这是干细胞的一个定义特征。在最近的工作中，我们和其他人开发了一种小鼠模型来研究胎儿微嵌合现象，并发现胎儿细胞在肺部的频率明显高于其他组织。在一项非凡的发现中，我们观察到大量与小鼠怀孕后出现的肺部肿瘤相关的胎儿细胞。我们对肺部胎儿微嵌合现象的观察使我们推测，怀孕后女性肺部中蕴藏的胎儿干细胞会影响女性肺癌的发展，要么通过增加女性患肺癌的易感性，要么恰恰相反，通过抑制肺部肿瘤的生长和发展。为了检验这一假设，我们将用两种转基因标记小鼠胎儿细胞，一种基因引发肺肿瘤，另一种编码荧光素酶。我们将对携带这些细胞的雌性小鼠进行光学成像，以筛选生物发光的肺部肿瘤。我们还将利用小鼠模型来探讨妊娠次数与肺癌发病率之间的关系。在另一项研究中，我们将从产下一个或多个男婴的女性的肺部肿瘤中提取 DNA 来筛查 Y 染色体的存在。从这项研究中获得的知识可能会导致基于胎儿细胞在肺部肿瘤发生中可能发挥的作用开发肺癌新疗法。特别是，如果胎儿细胞有助于肿瘤的发展，人们可以设想用有效靶向胎儿来源细胞的辅助疗法来治疗女性肺癌患者，从而保护健康组织。另一方面，如果我们发现胎儿细胞具有抑制肺部肿瘤生长的功能，那么这一发现可能成为开发新细胞疗法的基础。公共健康相关性：本研究的目的是检验以下假设：女性怀孕后很长时间内保留在肺部的胎儿干细胞可以通过增加女性患肺癌的易感性来影响女性肺癌的发展，或者恰恰相反，通过抑制肺部肿瘤的生长和发展。在考虑这项研究可能的临床应用时，如果我们发现胎儿细胞有助于肺部肿瘤的发展，这一知识将为开发新的肺癌基因疗法打开大门，该疗法将针对胎儿的死亡衍生的肿瘤细胞并保持健康的母体肺组织不受伤害。另一方面，如果我们发现证据表明胎儿细胞具有控制女性肺部肿瘤生长的功能，那么我们的发现可能会带来一种治疗肺癌的新型细胞疗法。