Prenatal stress and neuroblastoma development - is there a link?

 描述(申请人提供)：神经母细胞瘤(NB)是一种具有不同表型的儿童恶性肿瘤，范围从自发退化到高度侵袭性、无法治愈的肿瘤。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异常来解释。NB的产生是由于胎儿发育过程中交感神经元(SN)分化缺陷所致。引人注目的是，尽管存在遗传异常，但当受到适当因素的影响时，NB细胞会经历神经元分化。因此，分化缺陷似乎与基因变化无关，可能是由于胎儿环境的异常而引起的。引人注目的是，这两个促进去分化的因素 在母体应激期间，胎儿中的NB细胞、缺氧和糖皮质激素水平升高，这表明产前应激在NB的发育中起到了作用。此外，低氧和糖皮质激素都上调神经肽Y(NPY)，神经肽Y是交感神经递质，作为NB的有丝分裂和生存因子。与此一致，我们发现皮质酮治疗，以及使怀孕的小鼠受到与实验程序相关的压力，使其半合子TH-MYCN后代的肿瘤致瘤率从32%增加到。流行病学数据进一步支持了孕期母亲应激在促进新生儿发育中的作用。新生儿出生体重过低和过高都与NB的发生频率有关。低出生体重是产前压力的常见征兆，而高出生体重通常是由妊娠期糖尿病引起的。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分化受阻和神经母细胞积聚。这反过来又通过增强先前存在的突变的影响并促进进一步的基因变化的积累来促进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发育的影响；2)确定其作用的候选介体；3)阐明这种致瘤效应的机制。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。怀孕期间的母亲将受到长期的压力，并将比较她们产前压力过大和对照的半合子后代的肿瘤发生率。为了确定压力效应的中介因素，我们将确定压力诱导的已知压力中介物质浓度的变化，以及母亲及其后代的整体代谢变化。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。我们还将确定应激诱导的肿瘤表型和分子变化。据我们所知，这是第一项关于产前应激在新生儿发育中的作用的研究。如果成功，我们的研究将确定涉及NB病因学的新途径，这反过来可能为NB开辟新的治疗机会和先驱预防方法-无论是药理学还是行为学。

 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.