Clinically Aggressive Thyroid Cancer: Molecular Basis and Treatment Outcome

非甲状腺髓样癌（TCA）， 一种常见的内分泌恶性肿瘤，占大多数死亡 因为内分泌癌尽管大多数TCA都是 通过手术和放射性碘（I-131）成功治疗 消融治疗，与这种疾病相关的死亡率 多年来一直保持稳定，因为这些疗法 有效治疗临床侵袭性肿瘤， 生长模式和/或不能有效地捕获碘。这群 由分化差和间变性的TCA组成，但也 包括分化良好的TCA的某些亚组。的损失 恶性甲状腺细胞的碘捕获能力可能与 伴随着其他细胞和分子事件 去分化 我们的目标是研究 伴随临床侵袭性TCA的自然史， 各种分子标记物对标准治疗的反应 干预。术前诊断方法包括抽吸 细胞学、超声检查、甲状腺I-131扫描和/或 其他放射性核素，以及用L-甲状腺素进行抑制治疗。 具体问题包括：（一）优化诊断方法 TCA扫描及血清甲状腺球蛋白测定诊断 肿瘤复发，（ii）完善已经建立的方法， 给予I-131治疗以改善风险/效益比，（iii） 基于PCR的甲状腺特异性mRNA的检测和定量 (e.g.甲状腺球蛋白mRNA和其他标志物的mRNA）， 外周血中循环的甲状腺细胞，（iv）突变分析 TCA生长、凋亡和有丝分裂周期相关基因 促甲状腺激素受体、ras、p53、Fas/Fas等 配体和ret/PTC在原发性和转移性甲状腺肿瘤中， (v)体外培养TCAs永生化细胞系建立 问题研究存在或不存在的关系 分化标记和生长相关基因的突变， TCA的临床表现将有助于确定 负责甲状腺细胞的生长和分化，并指导 开发新的治疗策略， 通过将它们恢复为更良性的分化型， 表型。

Non-medullary thyroid cancer (TCA), the most common type of endocrine malignancy, accounts for most deaths due to endocrine cancers. Although the majority of TCAs are successfully managed with surgery and radioactive iodine (I-131) ablative therapy, the mortality associated with this disease has remained stable over the years because these therapies are not effective for clinically aggressive tumors, which have accelerated patterns of growth and/or fail to trap iodine efficiently. This group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs. The loss of iodine trapping ability by the malignant thyrocyte may be correlated with other cellular and molecular events that accompany de-differentiation. Our goal is to study the molecular events accompanying the natural history of clinically aggressive TCA and the response of various molecular markers to standard therapeutic intervention(s). Preoperative diagnostic methods include aspiration cytology, ultrasonography, thyroid scanning with I-131 and/or other radionuclides, and suppression therapy with L- thyroxine. Specific issues include: (i) optimization of methods of diagnostic scanning in TCA and serum thyroglobulin measurement to diagnose tumor recurrence, (ii) refinement of already established methods of administering I-131 therapy to improve the risk/benefit ratio, (iii) PCR-based detection and quantification of thyroid-specific mRNAs (e.g. thyroglobulin mRNA and mRNAs for other markers) in thyrocytes circulating in peripheral blood, (iv) analysis of mutations in genes involved in TCA growth, apoptosis, and mitotic cycle regulation, such as the thyrotropin receptor, ras, p53, Fas/Fas ligand, and ret/PTC in primary and metastatic thyroid tumors, and (v) establishment of immortalized cell lines from TCAs for in vitro studies. The relationship between the existence or absence of markers of differentiation and mutations in growth-relevant genes, and the clinical behavior of TCA will help define the pathways responsible for thyrocyte growth and differentiation, and guide the development of new therapeutic strategies to attack clinically aggressive TCAs by reverting them to a more benign differentiated phenotype.