ABSTRACT
Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Pan-genomic analyses identified p53/Rb and WNT/ß-catenin signaling pathways as main contributors to the disease. However, isolated ß-catenin constitutive activation failed to induce malignant progression in mouse adrenocortical tumors. Therefore, there still was a need for a relevant animal model to study ACC pathogenesis and to test new therapeutic approaches. Here, we have developed a transgenic mice model with adrenocortical specific expression of SV40 large T-antigen (AdTAg mice), to test the oncogenic potential of p53/Rb inhibition in the adrenal gland. All AdTAg mice develop large adrenal carcinomas that eventually metastasize to the liver and lungs, resulting in decreased overall survival. Consistent with ACC in patients, adrenal tumors in AdTAg mice autonomously produce large amounts of glucocorticoids and spontaneously activate WNT/ß-catenin signaling pathway during malignant progression. We show that this activation is associated with downregulation of secreted frizzled related proteins (Sfrp) and Znrf3 that act as inhibitors of the WNT signaling. We also show that mTORC1 pathway activation is an early event during neoplasia expansion and further demonstrate that mTORC1 pathway is activated in ACC patients. Preclinical inhibition of mTORC1 activity induces a marked reduction in tumor size, associated with induction of apoptosis and inhibition of proliferation that results in normalization of corticosterone plasma levels in AdTAg mice. Altogether, these data establish AdTAg mice as the first preclinical model for metastatic ACC.
Subject(s)
Adrenocortical Carcinoma/pathology , Antigens, Polyomavirus Transforming/genetics , Retinoblastoma Protein/physiology , Tumor Suppressor Protein p53/physiology , Animals , Humans , Mechanistic Target of Rapamycin Complex 1 , Mice , Mice, Transgenic , Multiprotein Complexes/physiology , Neoplasm Metastasis , Retinoblastoma Protein/antagonists & inhibitors , Sirolimus/pharmacology , TOR Serine-Threonine Kinases/physiology , Tumor Suppressor Protein p53/antagonists & inhibitors , Wnt Signaling Pathway/physiology , beta Catenin/physiologyABSTRACT
BACKGROUND & AIMS: : To determine if rapid growth between 0 and 2 years of life influences body composition and resting energy expenditure (REE) measured at 12-14 years in a population of obese children. METHODS: REE and body composition were measured in 107 obese children aged 12-14 years in whom weight at birth and 2 years was recorded. RESULTS: 46 obese children had a rapid growth between birth and 2 years (>0.67 SD). Rapid weight gain was positively correlated with weight and height at 12-14 years but not with body mass index (BMI). Fat mass (FM) to fat free mass (FFM) ratio was not significantly different at 12-14 years in children with rapid or normal growth velocity. REE in 12-14 year-old children with rapid growth (1765±222kcal/24h) was significantly higher than children with normal growth velocity (1586±216kcal/24h) (P<0.001). REE adjusted for FFM was similar in the two groups. CONCLUSIONS: Rapid weight gain between 0 and 2 years of life is associated with higher weight, height, FFM, FM and REE in 12-14 year-old obese children despite identical BMI. These data demonstrate that growth velocity affects later body composition and REE in obese adolescents but relationship between REE and FFM is preserved.