Clinically Aggressive Thyroid Cancer: Molecular Basis and Treatment Outcome

非甲状腺髓样癌（TCA）是最常见的内分泌恶性肿瘤，占内分泌癌死亡人数的大多数。尽管大多数TCA通过手术和放射性碘（I-131）消融治疗成功治疗，但多年来与这种疾病相关的死亡率保持稳定，因为这些治疗对临床侵袭性肿瘤无效。 后一组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，其具有加速的生长模式和/或不能有效地捕获碘。恶性甲状腺细胞碘捕获能力的丧失可能与伴随去分化的其他细胞和分子事件相关。我们的目标是研究伴随临床侵袭性TCA自然史的分子事件以及各种分子标志物对标准治疗干预的反应。术前诊断方法包括抽吸细胞学检查、超声检查、用I-131和/或其他放射性核素进行甲状腺扫描以及用L-甲状腺素进行抑制治疗。具体问题包括：（i）优化TCA和血清甲状腺球蛋白（Tg）测量的诊断扫描方法，以诊断肿瘤复发，（ii）完善已经建立的I-131治疗给药方法，以提高风险/效益比，（iii）基于PCR的甲状腺特异性mRNA检测和定量（例如甲状腺球蛋白mRNA和其它标志物的mRNA），（iv）分析涉及TCA生长、凋亡和有丝分裂周期调节的基因（例如促甲状腺激素受体）的突变，ras、p53、Fas/Fas配体和ret/PTC在原发性和转移性甲状腺肿瘤中的作用，以及（v）从人TCAs建立用于体外研究的永生化细胞系。分化标志物的表达水平以及生长相关基因的突变与TCA的临床行为之间的关系将有助于进一步确定负责甲状腺细胞生长和分化的途径。在过去的一年中，我们研究了钠碘同向转运体（NIS）的表达水平在乳头状TCA滤泡变异型患者的甲状腺原发性肾转移瘤中，并将其与体内I-131摄取相关。此外，我们回顾了31年的NIH（单一机构）的经验，在20例患者进行了广泛的二次手术切除的远端和局部转移，试图更好地定义他们的角色，在多模式管理的患者“临床上积极的”TCA。此外，我们与NCI同事合作，研究了一种新的促分化剂缩肽在诱导分化（即Tg和NIS mRNA的表达）中的作用，以及在体外分化不良的TCA细胞系中的杀肿瘤活性。我们的初步数据是令人鼓舞的作用，这种代理商，以及其他类似的代理商，临床上。事实上，我们目前正在开发干预性试验，旨在通过诱导/重新出现以前不存在的或目前肿瘤碘积累不足的情况，使侵袭性TCA恢复为更分化的表型，从而使其再次可通过131-I进行管理。

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. The latter group consists of poorly-differentated and anaplastic TCAs, but also includes certain sub-groups of well-differentiated TCAs, which have accelerated patterns of growth and/or fail to trap iodine efficiently. 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 (Tg) 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 human TCAs for in vitro studies. The relationship between the level of expression of markers of differentiation, as well as mutations in growth-relevant genes, and the clinical behavior of TCA will help further define the pathways responsible for thyrocyte growth and differentiation. Over the last year, we have studied the level of expression of sodium-iodide symporter (NIS) in renal metastases from thyroid primaries in patients with papillary TCA-Follicular Variant and correlated them with in vivo I-131 uptake. Further, we have reviewed 31 years of NIH (single institution) experience in 20 patients who underwent extensive secondary surgical resections of distant and locoregional metastases in an attempt to better define their role in the multimodality management of patients with "clinically aggressive" TCA. Additionally, in collaboration with our NCI colleagues, we have investigated the effects of a novel pro-differentiating agent, depsipeptide, in the induction of differentiation (i.e. expression of Tg and NIS mRNAs), and tumoricidal activity in poorly-differentiated TCA cell lines in vitro. Our preliminary data were encouraging for the role of this agent, as well as other similar agents, clinically. In fact, we are currently developing interventional trials aiming to revert aggressive TCAs to a more differentiated phenotype, by the induction/re-emergence of previously inexistent or the increase in currently insufficient iodine accumulation by the tumor, and thus rendering them yet again manageable by 131-I.