Abstract 3291: Prenatal stress increases neuroblastoma tumorigenesis in TH-MYCN mice model

Abstract

Abstract 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, 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 tumorigenesis. To test this hypothesis we used mice expressing MYCN oncogene under tyrosine hydroxylase promoter (TH-MYCN mice), which spontaneously develop NBs. To mimic stress, pregnant mothers carrying hemizygous TH-MYCN offspring were implanted with pellets containing either the main rodent glucocorticoid, corticosterone, or placebo at the time of neuroblast proliferation (embryonic days 10-20). Tumor frequency was compared between these two experimental groups and TH-MYCN offspring from intact pregnancies. Surprisingly, in pregnant mothers from the placebo group, physiological stress associated with experimental procedures alone (animal handling, blood collections, pellet insertion and anesthesia) was sufficient to elevate their corticosterone levels and increase tumorigenicity in their hemizygous TH-MYCN offspring from 32 to 64% (p = 0.03). A similar effect was observed in offspring of corticosterone-treated mothers with its levels comparable to mice eliciting a physiological stress response in the placebo group (<1200ng/ml). This stress-induced increase in tumorigenicity was associated with decreased tumor cell apoptosis, suggesting defects in neuroblast elimination as one of the mechanisms underlying this effect. While all female mice presented with ovarian metastases, tumor-bearing prenatally stressed offspring had increased frequency of other distant metastases (0% vs 71% for intact control and stressed groups respectively, p<0.05). No increase in tumorigenicity was observed in offspring of corticosterone-treated mothers having corticosterone levels markedly exceeding those observed in the placebo group (>1200ng/ml), indicating that only physiologically relevant levels of stress mediators can accurately recapitulate the stress response in animal models. Taken together, these findings support the role for prenatal stress in NB development, as well as implicate other pathologies associated with elevated levels of glucocorticoids in its etiology. Citation Format: Sung-Hyeok Hong, David Christian, Emily Trinh, Susana Galli, Meredith Horton, Yichien Lee, Christopher Albanese, Olga Rodriguez, Jason Ulip Tilan, Joanna Kitlinska. Prenatal stress increases neuroblastoma tumorigenesis in TH-MYCN mice model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3291. doi:10.1158/1538-7445.AM2015-3291