Project description:Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [adrenal]
Project description:Characterization of neuroendocrine tumors in heterozygous mutant MENX rats: a novel model of invasive medullary thyroid carcinoma [pituitary]
Project description:CDKN1B (p27) was formally established as a tumor suppressor gene (tsg) following the identification of inactivating germline mutations in rats (MENX syndrome) and patients (MEN4 syndrome) developing multiple neuroendocrine tumors (NETs). MENX-affected rats are homozygous for the predisposing p27 mutation, suggesting a canonical tsg function. In contrast, mice heterozygous for a defective Cdkn1b allele are already predisposed to tumor formation (haploinsufficiency). We here report that heterozygous mutant rats (p27+/mut) develop the same NETs seen in the homozygous (p27mut/mut) animals but with slower progression. In the tumors of p27+/mut rats, the wild-type allele is neither lost nor silenced, implying that p27 is haploinsufficient for tumor suppression also in this model. Transcriptome profiling of rat NETs having different p27 dosages revealed a tissue-specific, dose-dependent effect of p27 on gene expression. In p27+/mut rats, thyroid neoplasms progress to invasive and metastatic medullary thyroid carcinomas (MTCs) accompanied by increased calcitonin levels, as in humans. Comparison of expression signatures of late-stage versus early-stage MTCs from p27+/mut rats identified genes potentially involved in tumor aggressiveness. The expression of a subset of these genes was evaluated in human MTCs, and found associated with aggressive RET-M918T-positive tumors. Altogether, p27 haploinsufficiency in MENX rats uncovered a novel, representative model of invasive/metastatic MTC, exploitable for translational studies of this aggressive and often incurable cancer.
Project description:As overwhelming evidence coming from transgenic mouse models but also from MEN4 patients seem to suggest that loss or inactivation of a single p27 allele plays an important role in neuroendocrine tumorigenesis, we decided to perform a detailed analysis of the phenotype of rats heterozygous for the MENX-associated germline Cdkn1b mutation. We here show that the reduction to a single functional p27 allele predisposes MENX heterozygous rats to the development of neuroendocrine malignancies.
Project description:As overwhelming evidence coming from transgenic mouse models but also from MEN4 patients seem to suggest that loss or inactivation of a single p27 allele plays an important role in neuroendocrine tumorigenesis, we decided to perform a detailed analysis of the phenotype of rats heterozygous for the MENX-associated germline Cdkn1b mutation. We here show that the reduction to a single functional p27 allele predisposes MENX heterozygous rats to the development of neuroendocrine malignancies.
Project description:Male Sprague-Dawley rats were used to establish exhausted-exercise model by motorized rodent treadmill. Yu-Ping-Feng-San at doses of 2.18 g/kg was administrated by gavage before exercise training for 10 consecutive days. Quantitative proteomics was performed for assessing the related mechanism of Yu-Ping-Feng-San.
Project description:The radiolabelled somatostatin analogue 177Lu-octreotate is a promising treatment option for malignant neuroendocrine tumors that overexpress somatostatin receptors. The human small intestine neuroendocrine tumor cell line GOT1 and Medullary thyroid carcinoma model GOT2 have shown promising treatment response to 177Lu-octreotate in xenografted mice. In clinical studies, however, only low cure rates have been achieved to date. In xenografted tumors, the human stromal components have been replaced with mouse stroma, which may have an impact in the treatment response of the xenografts.
