Potential Role of Fetal Stem Cells in Lung Tumor Development

描述(申请人提供)：胎儿细胞在怀孕期间进入母体循环系统，并在血液和组织中保持低数量，可持续数年，甚至数十年。这种现象被称为胎儿微嵌合体。在怀孕期间进入母体循环的大多数胎儿细胞是造血源的，如有核的红细胞、淋巴细胞或造血干细胞。值得注意的是，研究表明，微嵌合胎儿细胞可以在怀孕很长时间后患有各种疾病的妇女的母体组织标本中表达上皮细胞、白细胞或肝细胞标记物。这一观察表明，胎儿细胞可能通过分化成多种细胞类型来对母体损伤做出反应，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个小鼠模型来研究胎儿微嵌合体，并发现肺中胎儿细胞的频率明显高于其他组织。在一项了不起的发现中，我们观察到了大量与怀孕后在小鼠体内发生的肺癌有关的胎儿细胞。我们对胎儿肺部微嵌合体的观察使我们假设，怀孕后女性肺部中藏匿的胎儿干细胞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，通过抑制肺癌的生长和发展。为了验证这一假设，我们将用两个转基因标记小鼠胚胎细胞，一个转基因引发肺部肿瘤，另一个编码荧光素酶。我们将对携带这些细胞的雌性小鼠进行光学成像，以筛选出生物发光的肺癌。我们还将使用小鼠模型来探索怀孕次数与肺癌发病率之间的关系。在另一项研究中，我们将对从生过男婴的妇女的肺肿瘤中提取的DNA进行Y染色体的筛查。从这项研究中获得的知识可能会导致基于胎儿细胞在肺肿瘤发生中所起作用的肺癌新疗法的开发。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治疗女性肺癌患者，从而节省健康组织。另一方面，如果我们发现胎儿细胞具有抑制肺癌生长的功能，这一发现可能成为开发新的细胞疗法的基础。 公共卫生相关性：这项研究的目的是检验这样一种假设，即怀孕后很长时间留在女性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，或者恰好相反，通过抑制肺癌的生长和发展。在考虑这项研究可能产生的临床应用时，如果我们发现胎儿细胞有助于肺癌的发展，这一知识将为开发基于基因的肺癌新疗法打开大门，这种疗法将针对胎儿来源的肿瘤细胞的死亡，并使健康的母体肺组织不受损害。另一方面，如果我们发现证据表明，胎儿细胞能够抑制女性肺癌的生长，我们的发现可能会导致一种治疗肺癌的新的细胞疗法。

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.