Chenlo Miguel, Bernabeu Ignacio, Korbonits Márta, Alvarez Clara V
Endocr Relat Cancer. 2025 Jan 23;32(3). doi: 10.1530/ERC-24-0156. Print 2025 Mar 1.
The discovery of RET mutations in multiple endocrine neoplasia type 2A (MEN2A) in 1993 ignited a revolution in our understanding of this versatile receptor. Since then, the influence of RET has expanded to encompass diverse organs, including the pituitary gland. This review explores the multifaceted role of RET in somatotrophs, focusing on two opposing pathways: proliferation versus differentiation and apoptosis. The binding of glial-derived neurotrophic factor (GDNF) to RET promotes pituitary cell survival and inhibits PIT1-dependent differentiation, while low levels of GDNF trigger differentiation via PIT1. Excessive PIT1, on the other hand, will lead to apoptosis through caspase-3 activation involving the adaptor protein AIP and CDKN2A-ARF/p53. Pathogenic mutations in AIP can disrupt this apoptotic pathway, contributing to somatotrophinoma or prolactinoma development. In this concise review, we highlight the potential of CDKN2A-ARF expression as a prognostic marker for therapy response and discuss the promise of novel RET tyrosine kinase inhibitors for aggressive somatotrophinomas.
1993年在2A型多发性内分泌腺瘤（MEN2A）中发现RET突变，引发了我们对这种多功能受体认识的一场革命。从那时起，RET的影响范围不断扩大，涵盖了包括垂体在内的多种器官。本综述探讨了RET在生长激素细胞中的多方面作用，重点关注两条相反的途径：增殖与分化以及细胞凋亡。胶质细胞源性神经营养因子（GDNF）与RET的结合促进垂体细胞存活并抑制PIT1依赖的分化，而低水平的GDNF则通过PIT1触发分化。另一方面，过量的PIT1会通过涉及衔接蛋白AIP和CDKN2A-ARF/p53的半胱天冬酶-3激活导致细胞凋亡。AIP中的致病突变会破坏这种凋亡途径，导致生长激素瘤或催乳素瘤的发生。在这篇简短的综述中，我们强调了CDKN2A-ARF表达作为治疗反应预后标志物的潜力，并讨论了新型RET酪氨酸激酶抑制剂对侵袭性生长激素瘤的治疗前景。
