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）消融治疗得以成功治疗，但由于这些疗法对临床侵袭性肿瘤无效，与该疾病相关的死亡率多年来一直保持稳定。后一类由分化差和间变性的tca组成，但也包括某些分化良好的tca亚群，它们的生长模式加快和/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有关。我们的目标是研究伴随临床侵袭性TCA自然史的分子事件，以及各种分子标记物对标准治疗干预的反应。术前诊断方法包括吸痰细胞学检查、超声检查、碘-131和/或其他放射性核素甲状腺扫描和l -甲状腺素抑制治疗。具体问题包括：(i)优化TCA的诊断扫描方法和血清甲状腺球蛋白（Tg）测量方法，以诊断肿瘤复发；（ii）改进已建立的i -131治疗方法，以提高风险/效益比；（iii）基于pcr的检测和定量外周血循环甲状腺细胞中甲状腺特异性mRNA（如甲状腺球蛋白mRNA和其他标志物mRNA）； （iv）分析与TCA生长、凋亡相关的基因突变；和有丝分裂周期调节，如促甲状腺素受体、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)建立用于体外研究的人TCAs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甲状腺细胞生长和分化的途径。在过去的一年里，我们研究了乳头状tca -滤泡变异患者甲状腺原发肾转移灶中碘化钠同调体（NIS）的表达水平，并将其与体内I-131摄取联系起来。此外，我们回顾了31年来美国国立卫生研究院（NIH）对20例患者的研究经验，这些患者接受了广泛的远处和局部转移的二次手术切除，试图更好地定义他们在“临床侵袭性”TCA患者的多模式管理中的作用。此外，我们与NCI的同事合作，在体外研究了一种新的促分化剂——沉积肽在诱导分化（即Tg和NIS mrna的表达）和低分化TCA细胞系的杀瘤活性方面的作用。我们的初步数据对这种药物以及其他类似药物的临床作用是令人鼓舞的。事实上，我们目前正在开展干入性试验，旨在通过诱导/重新出现先前不存在的肿瘤或增加目前不足的肿瘤碘积累，使侵袭性tca恢复到更分化的表型，从而使它们再次受到131-I的控制。

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.