Powers James F, Brachold Jaime M, Tischler Arthur S
Department of Pathology, Tufts-New England Medical Center, 750 Washington Street, Boston, MA 02111, USA.
Endocr Pathol. 2003 Winter;14(4):351-61. doi: 10.1385/ep:14:4:351.
Ret is a developmentally regulated tyrosine kinase involved in formation and maintenance of the nervous system. Ret mutations predisposing to pheochromocytomas and medullary thyroid carcinomas occur in multiple endocrine neoplasia (MEN) syndromes 2A and 2B. Biochemical studies have demonstrated overexpression of Ret mRNA and protein in pheochromocytomas compared to normal adrenal medulla. However, the cellular distribution of Ret in the normal human adrenal and in hyperplastic lesions that antecede pheochromocytomas are unclear. The present investigation was undertaken to resolve the histological distribution of Ret in the normal human adrenal, in pheochromocytomas evolving from adrenal medullary hyperplasia in MEN2A and in sporadic pheochromocytomas. Ret expression was studied by immunohistochemistry using both a polyclonal and a monoclonal antibody, with confirmation by immunoblotting of representative cases. Only occasional cells stained for Ret in the normal adrenal, consistent with the distribution in adult adrenals of other species. Heterogeneous, progressively increased Ret expression was observed during the evolution of pheochromocytomas. In both normal and neoplastic adrenal, the most intense immunoreactivity was observed in cells with neuron-like features. Our finding that Ret is not expressed at high levels in the early stages of disease suggests that elucidation of mechanisms that regulate Ret expression is required for understanding the pathobiology of MEN2A. The association of high-level Ret expression with neuronal morphology suggests that the variable overexpression of Ret in pheochromocytomas might in part be an epiphenomenon, reflecting the known phenotypic plasticity of these tumors.
Ret是一种在发育过程中受到调控的酪氨酸激酶，参与神经系统的形成和维持。易患嗜铬细胞瘤和甲状腺髓样癌的Ret突变发生在多发性内分泌腺瘤（MEN）2A和2B综合征中。生化研究表明，与正常肾上腺髓质相比，嗜铬细胞瘤中Ret mRNA和蛋白表达上调。然而，Ret在正常人类肾上腺以及嗜铬细胞瘤之前的增生性病变中的细胞分布尚不清楚。本研究旨在明确Ret在正常人类肾上腺、MEN2A中由肾上腺髓质增生演变而来的嗜铬细胞瘤以及散发性嗜铬细胞瘤中的组织学分布。通过使用多克隆抗体和单克隆抗体的免疫组织化学方法研究Ret表达，并通过对代表性病例的免疫印迹进行确认。在正常肾上腺中，仅偶尔有细胞被Ret染色，这与其他物种成年肾上腺中的分布一致。在嗜铬细胞瘤的演变过程中观察到Ret表达呈异质性且逐渐增加。在正常和肿瘤性肾上腺中，在具有神经元样特征的细胞中观察到最强的免疫反应性。我们的发现表明，在疾病早期Ret不高表达，这提示为了理解MEN2A的病理生物学，需要阐明调节Ret表达的机制。Ret高表达与神经元形态的关联表明，嗜铬细胞瘤中Ret的可变过表达可能部分是一种附带现象，反映了这些肿瘤已知的表型可塑性。
