Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer.
Thyroid-stimulating hormone receptor (TSHR) as a target for imaging differentiated thyroid cancer.
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促甲状腺激素受体（TSHR）作为分化型甲状腺癌成像的靶点。
作者：
Gimblet,GraysonR;Whitt,Jason;Houson,HaileyA;Lin,Diana;Guenter,Rachael;Rao,TejeshwarC;Wang,Dezhi;Ness,John;Gonzalez,ManuelLora;Murphy,MadisenS;Gillis,Andrea;Chen,Herbert;Copland,JohnA;Kenderian,SaadS;Lloyd,RicardoV;Szk
在每年诊断的50万例甲状腺癌中，95%为分化型甲状腺癌。尽管临床指南建议手术切除后进行放射性碘消融，但钠-碘同向转运体表达的缺失导致高达20%的分化型甲状腺癌成为放射性碘难治性甲状腺癌。对于放射性碘难治性疾病患者，迫切需要新的诊断和治疗方法。我们评估的促甲状腺激素受体作为一个潜在的目标，分化型甲状腺cancer.MethodsWe免疫染色组织微阵列含有52 Hurthle细胞癌，以确认促甲状腺激素受体的表达成像。我们用放射性标记螯合剂去铁胺与重组人促甲状腺激素类似物超激动剂TR 1402偶联（t1/2= 78.4 h，β+=22.7%）以产生[89 Zr] Zr-TR 1402。我们在高促甲状腺激素受体和低促甲状腺激素受体表达的THJ 529 T和FTC 133甲状腺癌细胞系中进行了体外摄取试验。我们进行了体内正电子发射断层扫描/计算机断层扫描和生物分布的研究，在雄性无胸腺裸鼠携带促甲状腺激素受体阳性THJ 529 T tumors. ResultsImmunohistochemistry分析显示62%的患者（27原发性和5复发）是促甲状腺激素受体膜免疫染色阳性。在促甲状腺激素受体阳性THJ 529 T甲状腺癌细胞系中，1 nM [89 Zr] Zr-TR 1402的体外摄取为38 ± 17%结合/mg，而在低表达细胞系中为3.2 ± 0.5（P< .01），在FTC 133细胞系中观察到类似差异（P< .0001）。体内和生物分布研究表明，[89 Zr] Zr-TR 1402在促甲状腺激素受体表达肿瘤中的摄取，注射后第3天注射剂量/g的平均百分比为1.9 ± 0.4。结论我们观察到促甲状腺激素受体在组织微阵列中的表达和[89 Zr] Zr-TR 1402在促甲状腺激素受体中的积累。阳性甲状腺癌细胞和肿瘤表明促甲状腺激素受体是分化型甲状腺癌成像的有希望的靶点。
BackgroundOf the half a million cases of thyroid cancer diagnosed annually, 95% are differentiated thyroid cancers. Although clinical guidelines recommend surgical resection followed by radioactive iodine ablation, loss of sodium–iodine symporter expression causes up to 20% of differentiated thyroid cancers to become radioactive iodine refractory. For patients with radioactive iodine refractory disease, there is an urgent need for new diagnostic and therapeutic approaches. We evaluated the thyroid-stimulating hormone receptor as a potential target for imaging of differentiated thyroid cancer.MethodsWe immunostained tissue microarrays containing 52 Hurthle cell carcinomas to confirm thyroid-stimulating hormone receptor expression. We radiolabeled chelator deferoxamine conjugated to recombinant human thyroid-stimulating hormone analog superagonist TR1402 with89Zr (t1/2= 78.4 h,β+=22.7%) to produce [89Zr]Zr-TR1402. We performed in vitro uptake assays in high–thyroid-stimulating hormone receptor and low–thyroid-stimulating hormone receptor–expressing THJ529T and FTC133 thyroid cancer cell lines. We performed in vivo positron emission tomography/computed tomography and biodistribution studies in male athymic nude mice bearing thyroid-stimulating hormone receptor–positive THJ529T tumors.ResultsImmunohistochemical analysis revealed 62% of patients (27 primary and 5 recurrent) were thyroid-stimulating hormone receptor membranous immunostain positive. In vitro uptake of 1nM [89Zr]Zr-TR1402 was 38 ± 17% bound/mg in thyroid-stimulating hormone receptor–positive THJ529T thyroid cancer cell lines compared to 3.2 ± 0.5 in the low-expressing cell line (P< .01), with a similar difference seen in FTC133 cell lines (P< .0001). In vivo and biodistribution studies showed uptake of [89Zr]Zr-TR1402 in thyroid-stimulating hormone receptor–expressing tumors, with a mean percentage of injected dose/g of 1.9 ± 0.4 at 3 days post-injection.ConclusionOur observation of thyroid-stimulating hormone receptor expression in tissue microarrays and [89Zr]Zr-TR1402 accumulation in thyroid-stimulating hormone receptor–positive thyroid cancer cells and tumors suggests thyroid-stimulating hormone receptor is a promising target for imaging of differentiated thyroid cancer.