Bagheri-Yarmand Rozita, Grubbs Elizabeth G, Hofmann Marie-Claude
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Recent Results Cancer Res. 2025;223:51-91. doi: 10.1007/978-3-031-80396-3_3.
The thyroid parafollicular cell, or commonly named "C-cell," functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of RB1 regulatory pathway as potential mediators of C-cell transformation. More recently, the integration of multiple biological layers of omics studies has uncovered new pathways of oncogenesis. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation, will help in the development of novel molecular targeted therapies.
甲状腺滤泡旁细胞，通常称为“C细胞”，在血清钙稳态中发挥作用。血清钙升高会触发C细胞释放降钙素，而降钙素反过来又会抑制肠道对钙的吸收、破骨细胞对骨的重吸收以及肾小管细胞对钙的重吸收。甲状腺C细胞的致癌转化被认为在恶变之前会经历一个增生过程，血清降钙素水平的升高可作为肿瘤负荷的生物标志物。2型多发性内分泌肿瘤由RET基因的激活突变引起，这一发现突出了RET-RAS-MAPK信号通路在甲状腺髓样癌发生和发展中的作用。已知甲状腺C细胞相对于大多数细胞类型高水平表达RET，因此该受体的异常激活主要靶向C细胞，这为组织特异性肿瘤发生提供了一个可能的原因。虽然降钙素基因转录似乎对RET激活敏感，但RET信号在正常C细胞功能中的作用尚不清楚。除了RET之外，动物肿瘤发生模型和人类肿瘤候选基因突变筛查发现RAS家族成员突变和RB1调节通路失活是C细胞转化的潜在介质。最近，多组学研究的多个生物学层面的整合揭示了新的肿瘤发生途径。越来越多地了解RET如何在正常C细胞功能和致癌转化过程中与这些途径相互作用，将有助于开发新的分子靶向疗法。
