分化型甲状腺癌131I WBS阴性/Tg阳性病灶葡萄糖代谢及其TSH调控和TSH受体表达的研究

Local recurrence and distant metastases are common in differentiated thyroid carcinoma (DTC) after surgery. Metastatic disease is a factor that worsens prognosis of DTC patients. Therefore, the long-term monitoring of patients with DTC is essential throughout the patient’s life after total or nearly total thyroidectomy followed by 131I remnant ablation and thyroid hormone suppression of thyroid-stimulating hormone (TSH). Serum thyroglobulin (Tg) levels during thyroid hormone withdrawal usually are correlated well with the results of 131I diagnostic whole-bodyscanning (DWBS). However, differentiated thyroid carcinoma with Tg positive and 131I negative metastases (131IWBS–/Tg+) has been observed in follow-up studies. 18FDG-PET has been more commonly used in the diagnosis of DTC with 131IWBS–/Tg+. However, we observed that 18FDG-PET has limited value in the diagnosis of DTC with 131IWBS–/Tg+, and the flip-flop phenomena of 18FDG and 131I uptake, an inverse relationship was found between uptake of 18FDG and 131I in most DTC metastases, a phenomenon termed ‘flip-flop’-namely, functional tumor differentiation is associated with low 18F-FDG uptake and retaining 131I uptake, whereas dedifferentiation is associated with the loss of iodine-accumulating ability and an increase in metabolism from progressive growth. Our previous study showed that the effects of TSH stimulation on the uptake of FDG for DTC with Tg-positive and radioactive iodine-negative metastases remains controversial. Our basic research also found that the TSH receptor expression significantly decreased in DTC cell line FTC-133 after the low doses of 131I radiation. The dedifferentiated cell line of DTC transfected with TSH receptor had increased iodine uptake. These studies suggest that glucose metabolism may be associated with iodine metabolism in 131IWBS–/Tg+ lesions. The sensitivity of 18FDG-PET imaging is not only correlated with energy metabolism of glucose (aerobic oxidation and anaerobic glycolysis) in the different location of DTC metastases and its TSH regulation, but also the TSH receptor expression in 131IWBS–/Tg+ lesions. Based on the previous studies, the project aims to study the energy metabolism of glucose (aerobic oxidation and anaerobic glycolysis) in 131IWBS–/Tg+ lesions and its regulation of TSH, TSH receptor expression in order to further understand the causes for 131IWBS–/Tg+ lesions, to clarify the correlation between iodine and glucose metabolism, finally to establish the relationship between TSH regulation and 18FDG-PET imaging. Our study will also lay foundation for the development of new targets and anti-tumor drugs.

10-15%的分化型甲状腺癌(DTC)病人出现131I显像阴性和Tg阳性（IWBS–/Tg+），这是最为棘手的临床问题，因为只有定性诊断而无定位依据。前期研究中通过甲状腺原位注射，我们建立了DTC及其转移灶模型。并发现IWBS–/Tg+病灶的葡萄糖和碘代谢之间有关联；FDG PET诊断敏感性不仅与转移部位的葡萄糖转运体表达及其TSH调控有关，还可能与TSH受体表达有关。在此研究基础上，拟通过18F-FDG和11C-乙酸盐显像，14C/3H-葡萄糖研究DTC病灶中葡萄糖有氧氧化和无氧酵解与显像结果、和其TSH调控以及TSH受体表达相关性研究，以进一步了解IWBS–/Tg+发生原因，阐明葡萄糖和碘代谢之间及其TSH调控和FDG PET显像的关系，为寻找新的葡萄糖代谢差异靶点、诱导再分化和抗肿瘤靶点药物的开发提供理论依据。

一、背景：10-15%的分化型甲状腺癌(DTC)病人出现131I显像阴性和Tg阳性（IWBS–/Tg+），这是临床棘手问题，因为只有定性诊断而无定位依据。IWBS–/Tg+病灶的葡萄糖和碘代谢之间有关联；FDG PET诊断敏感性不仅与转移部位的葡萄糖转运体表达及其TSH调控有关，还可能与TSH受体表达有关。在此研究基础上，拟通过研究DTC病灶中葡萄糖和碘代谢与显像结果、和其TSH调控以及TSH受体表达相关性研究，以进一步了解IWBS–/Tg+发生原因，阐明葡萄糖和碘代谢之间及其TSH调控和FDG PET显像的关系。.二、本项目主要研究内容： 通过研究131IWBS–/Tg+ 复发或转移灶葡萄糖代谢及其TSH调控，以进一步了解131I WBS-/Tg+发生原因，阐明葡萄糖和碘代谢及其TSH调控和18FDG-PET显像诊断阳性或阴性的关系。1. 改进DTC模型建模方法：采用DTC肿瘤组织进行造模并进行FDG PET/CT和131I WBS。2. 分化型甲状腺癌不同转移部位的转移灶葡萄糖代谢和碘代谢研究。3. 分化型甲状腺癌TSH与垂体FDG摄取相关性研究。4. 分化型甲状腺癌术后甲状旁腺功能减退对骨密度的影响，双膦酸盐药物治疗绝经后DTC病人的骨量减少和骨质疏松。5. 同位素标记的膦酸盐药物抗骨质疏松、治疗股骨头坏死和距骨坏死的基础和临床研究。6. SLPI的生物信息学分析、组蛋白家族基因在BC中的表达及潜在的预后价值。.三、重要结果和关键数据及科学意义：采用DTC肿瘤组织成功造模，为后续稳定建模研究其碘和葡萄糖代谢以及免疫治疗提供依据；甲状腺癌不同转移部位葡萄糖和碘代谢存在异质性，骨转移呈现碘和葡萄糖均高代谢，淋巴结和肺转移存在反转现象； 垂体FDG摄取与血清TSH呈正相关；绝经后DTC患者短暂性甲状旁腺功能低下其腰椎骨密度升高，TSH抑制治疗后降低绝经后DTC患者骨密度，双膦酸盐药物可以有效治疗绝经后DTC患者骨质疏松；同位素标记的膦酸盐药物具有更好的抗骨质疏松、治疗股骨头坏死和距骨坏死；SLPI可以作为预测BC预后的生物标志物，组蛋白基因组可以用作预测BC患者生存的预后因素。