Prenatal stress and neuroblastoma development - is there a link?

产前压力和神经母细胞瘤的发育——有联系吗？

• 批准号: 8958817
• 负责人: Joanna B. Kitlinska
• 金额: $ 20.29万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8958817
• 关键词: Address; Affect; Apoptosis; Behavioral; Birth; Birth Weight; Cell Hypoxia; Cells; Chronic; Chronic stress; Clinical; Cognitive; Control Animal; Corticosterone; Cues; DNA Sequence Alteration; Data; Defect; Development; Differentiation Inducer; Disease; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Epigenetic Process; Equilibrium; Etiology; Fetal Development; Fetus; Figs - dietary; Foundations; Frequencies; Ganglia; Genetic; Gestational Diabetes; Glucocorticoids; Hereditary Disease; Heterogeneity; Hormones; Hydrocortisone; Hyperplasia; Hypoxia; Inherited; Intervention; Link; Low Birth Weight Infant; MYCN gene; Malignant - descriptor; Malignant Childhood Neoplasm; Mediator of activation protein; Messenger RNA; Metabolic; MicroRNAs; Modality; Modeling; Molecular; Molecular Abnormality; Mothers; Mus; Mutation; Nature; Neural Crest Cell; Neuroblastoma; Neuronal Differentiation; Neurons; Neurotransmitters; Pathway interactions; Pediatric Neoplasm; Penetrance; Pharmacological Treatment; Phenotype; Plasma; Population; Population Control; Populations at Risk; Precancerous Conditions; Pregnancy; Pregnant Women; Procedures; Process; Proliferating; Property; Proteins; Research; Risk; Role; Stress; Sympathetic Ganglia; Sympathetic Nerve Block; Testing; Tumor-Derived; Tumorigenicity; Urine; base; design; differential expression; embryonic stem cell; fetal; fetus hypoxia; inhibitor/antagonist; maternal stress; metabolomics; neoplastic cell; neuroblast; neuroblastoma cell; neurogenesis; neuron development; neuropeptide Y; non-genetic; novel; novel therapeutics; offspring; outcome forecast; pregnant; prenatal exposure; prenatal stress; public health relevance; receptor; stress management; tumor; tumorigenic

 DESCRIPTION (provided by applicant): Neuroblastomas (NB) are pediatric malignancies with heterogenous phenotypes, ranging from spontaneously regressing to highly aggressive, incurable tumors. Although NB is considered a genetic disease, its etiology and heterogeneity cannot be explained solely by genetic aberrations. NB arises due to defects in sympathetic neuron (SN) differentiation occurring during fetal development. Strikingly, despite the presence of genetic aberrations, NB cells undergo neuronal differentiation when subjected to proper factors. Thus, differentiation defects seem to be independent of genetic changes and can arise due to abnormalities in fetal environment. Strikingly, the two factors promoting de-differentiation of NB cells, hypoxia and glucocorticoids, are elevated in the fetus during maternal stress, suggesting a role for prenatal stress in NB development. Moreover, both hypoxia and glucocorticoids up-regulate neuropeptide Y (NPY), the sympathetic neurotransmitter acting as a mitogenic and survival factor for NB. In line with this, we have found that corticosterone treatment, as well as subjecting pregnant mice to stress associated with experimental procedures alone, increased tumorigenicity in their hemizygous TH-MYCN offspring from 32 to 64%. The role of maternal stress during pregnancy in promoting NB development is further supported by epidemiological data. Increased frequency of NB has been associated with low and high birth weights. Low birth weight is a common sign of prenatal stress, while high birth weight is most often caused by gestational diabetes. Notably both of these conditions are associated with elevated fetal cortisol. Hence, we hypothesize that prenatal stress leads to the blocking of SN differentiation and accumulation of neuroblasts by changing the fetal microenvironment. This, in turn, promotes NB formation by augmenting effects of pre-existing mutations and facilitating accumulation of further genetic changes. To test our hypothesis, we will 1) Determine the effect of prenatal stress on NB development; 2) Identify candidate mediators of its actions and 3) Elucidate the mechanism of this tumorigenic effect. To test the effect of prenatal stress on NB development we will use TH-MYCN mice, which spontaneously develop NB. The mothers during pregnancy will be chronically stressed and tumor frequencies will be compared between their prenatally-stressed and control hemizygous offspring. To identify mediators of the stress effect, we will determine stress-induced changes in concentrations of known stress mediators and overall metabolic alterations in mothers and their offspring. Then, we will test the impact of the candidate stress mediators on SN differentiation, as well as proliferation and survival of neuroblasts and NB cells from prenatally stressed and control animals. We will also determine stress-induced phenotypic and molecular changes in tumors. To our knowledge, this is the first study addressing the role for prenatal stress in NB development. If successful, our research will identify novel pathways involved in NB etiology, which in turn may open new therapeutic opportunities and pioneer preventative approaches for NB - both pharmacological and behavioral.

 描述（由申请方提供）：神经母细胞瘤（NB）是具有异质性表型的儿科恶性肿瘤，范围从自发性消退到高度侵袭性、不可治愈的肿瘤。虽然NB被认为是一种遗传性疾病，但其病因和异质性不能仅用遗传畸变来解释。NB的出现是由于胎儿发育过程中发生的交感神经元（SN）分化缺陷。引人注目的是，尽管存在遗传畸变，NB细胞进行神经元分化时，受到适当的因素。因此，分化缺陷似乎是独立的遗传变化，并可能出现由于胎儿环境的异常。引人注目的是，促进去分化的两个因素 NB细胞，缺氧和糖皮质激素，在母体压力期间胎儿升高，提示产前压力在NB发展中的作用。此外，缺氧和糖皮质激素上调神经肽Y（NPY），交感神经递质作为有丝分裂和生存因子NB。与此一致，我们发现皮质酮治疗，以及使怀孕的小鼠受到与单独的实验程序相关的压力，使其半合子TH-MYCN后代的致瘤性从32%增加到64%。流行病学数据进一步支持了妊娠期母体压力在促进NB发展中的作用。NB发生频率的增加与出生体重的高低有关。低出生体重是产前压力的常见迹象，而高出生体重最常见的是由妊娠糖尿病引起的。值得注意的是，这两种情况都与胎儿皮质醇升高有关。因此，我们假设产前应激通过改变胎儿微环境导致SN分化和成神经细胞积累受阻。这反过来又通过增强预先存在的突变的影响和促进进一步遗传变化的积累来促进NB的形成。为了验证我们的假设，我们将1）确定产前应激对NB发展的影响; 2）确定其作用的候选介质; 3）阐明这种致瘤作用的机制。为了测试产前应激对NB发育的影响，我们将使用自发发育NB的TH-MYCN小鼠。怀孕期间的母亲将长期受到压力，并将在产前压力和对照半合子后代之间比较肿瘤频率。为了确定应激效应的介质，我们将确定已知应激介质浓度的应激诱导变化以及母亲及其后代的总体代谢变化。然后，我们将测试候选应激介质对SN分化的影响，以及来自产前应激和对照动物的神经母细胞和NB细胞的增殖和存活。我们还将确定肿瘤中应激诱导的表型和分子变化。据我们所知，这是第一个研究解决产前压力在NB发展中的作用。如果成功，我们的研究将确定涉及NB病因的新途径，这反过来可能为NB开辟新的治疗机会和先驱预防方法-药理学和行为学。