CN116836916A - 用于预测分化型甲状腺癌摄碘能力的类器官、系统及方法 - Google Patents
用于预测分化型甲状腺癌摄碘能力的类器官、系统及方法 Download PDFInfo
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Abstract
本发明属于医学检测领域,具体公开了用于预测分化型甲状腺癌摄碘能力的类器官、系统及方法。本发明一种用于预测分化型甲状腺癌摄碘能力的类器官培养方法,它包括以下步骤:取甲状腺组织,切碎,加消化液消化,研磨过滤,离心,取沉淀加Matrigel混匀,凝固后加类器官增殖培养基培养,即得。本发明预测系统包括分化型甲状腺癌类器官、正常甲状腺类器官和甲状腺髓样癌类器官,该系统用于分化型甲状腺癌术后摄碘能力预测,结果准确,具备广阔的应用前景。
Description
技术领域
本发明属于医学检测领域,具体涉及一种用于预测分化型甲状腺癌摄碘能力的类器官、系统及方法。
背景技术
甲状腺癌中95%以上为分化型甲状腺癌(DTC),其保留了甲状腺滤泡上皮细胞摄取碘的能力,在甲状腺全切+术后131I治疗+促甲状腺激素抑制治疗的综合管理下,大部分患者可达到长期无病生存。然而,约60-70%的远处转移DTC患者可出现摄碘能力差或不摄碘,成为放射性碘难治性DTC(RAIR-DTC)。由于缺乏有效的评估手段,DTC术后患者都在病灶摄碘状态未知的情况下进行131I治疗。如何早期精准识别病灶摄碘能力良好的患者给予治疗,避免不必要的辐射伤害,是DTC诊疗中亟待解决的问题。目前除通过DTC术后进行131I全身显像直接观察病灶摄碘状态外,无其他提前预测分化型甲状腺癌患者病灶摄碘能力的方法。
类器官指利用干细胞、祖细胞或分化细胞进行体外培养,形成具有3D结构的组织类似物,可在体外重现原始组织的结构和功能。目前,已经成功培养出了结直肠癌、胃癌、胰腺癌等多种恶性肿瘤来源的类器官,并将其用于探索肿瘤驱动及疾病演进规律、药物开发、肿瘤精准治疗等。现有研究提示肿瘤类器官可以预测患者对放化疗等抗癌治疗的敏感性,且类器官药物敏感试验已应用于多种肿瘤的临床治疗方案指导。类器官模型在多种疾病研究及临床诊疗中展现出强大的应用潜力,但在核医学领域仍为空白。甲状腺肿瘤相对增殖能力低,类器官培养困难,现有文献中针对分化型甲状腺癌类器官的培养基以及培养方法的研究较少,且所培育的类器官难以在体外长期稳定传代,此外,目前还没有成功获得甲状腺髓样癌类器官的相关研究,更无甲状腺类器官用于预测分化型甲状腺患者体内病灶的摄碘能力的报道。
发明内容
为了准确评估分化型甲状腺癌患者术后病灶的摄碘能力, 本发明提供了一种用于预测分化型甲状腺癌摄碘状态的类器官培养方法它包括以下步骤:
取甲状腺组织,切碎,加消化液消化,研磨过滤,离心,取沉淀加Matrigel混匀,凝固后加类器官增殖培养基培养,即得;
所述类器官增殖培养基是含1:100 N2,1:50 B27,50ng/mL EGF, 100ng/mL FGF,50ng/mL HGF, 10mmol/L Nicotinamide,1.25mmol/LN-acetylcysteine,10μmol/L Y-27632,5μmol/L A83-01,5μmol/L SB202190,1:10 R-spondin, 1:10 Noggin,1:10 Wnt3a,1% PS,1% Glutamax和 1%Hepes的DMEM/F12培养基。
进一步地,所述组织切碎至1mm*1mm*1mm;所述消化液是含500 µg/mlCollagenase type XI和 200 µg/ml Dnase-1的1% DMEM/F12溶液;所述消化的温度37℃,时间0.5-1小时;所述离心的速度800rpm,时间5min;所述沉淀见红色,用红细胞裂解液20-25℃处理2min,800rpm离心5min,去上清液;所述培养的温度为37℃ ,时间2周。
本发明还提供了一种用于预测分化型甲状腺癌术后摄碘能力的类器官,它是分化型甲状腺癌组织、正常甲状腺组织和甲状腺髓样癌组织按照前述方法制备而成的类器官。
本发明还提供了一种前述类器官在制备分化型甲状腺癌术后摄碘能力的预测系统中的用途。
本发明还提供了一种分化型甲状腺癌术后摄碘能力的预测系统,它包括:
1)甲状腺相关类器官;
所述甲状腺相关类器官为前述类器官的第2代;
2)摄碘试验相关仪器和试剂;
3)甲状腺相关类器官摄取131I后放射性辐射数据的采集装置;
4)放射性辐射数据的分析装置。
进一步地,所述仪器包括细胞培养板;试剂包括Na131I溶液、PBS溶液和NaOH溶液。
进一步地,所述采集装置包括伽马计数仪。
进一步地,所述摄碘能力分为轻度摄碘和摄碘能力良好;所述轻度摄碘的分化型甲状腺癌类器官放射性计数大于等于150 CPM/105cells;所述摄碘能力良好的分化型甲状腺癌类器官放射性计数大于等于300 CPM/105cells;所述摄碘能力预测结果准确时正常甲状腺类器官放射性计数大于500 CPM/105cells,甲状腺髓样癌放射性计数小于50 CPM/105cells。
本发明还提供了一种前述类器官在预测分化型甲状腺癌术后摄碘能力中的用途。
本发明最后提供了一种预测分化型甲状腺癌术后摄碘能力的方法,它包括如下步骤:
分别取甲状腺相关类器官,加Na131I溶液孵育,除去上清,清洗后加NaOH溶液裂解细胞,采用伽马计数仪测量放射性计数;
所述甲状腺相关类器官为前述类器官的第2代;
所述类器官中分化型甲状腺癌类器官放射性计数大于等于150 CPM/105cells为轻度摄碘,放射性计数大于等于300 CPM/105cell为摄碘能力良好;正常甲状腺类器官放射性计数大于500 CPM/105cells,甲状腺髓样癌类器官放射性计数小于50 CPM/105cells,摄碘能力预测结果准确。
进一步地,所述类器官在孔板中每孔加100uL Na131I溶液;所述Na131I溶液浓度为1uCi/mL,孵育温度为37℃;所述孵育的时间为60min;所述清洗是用37℃ PBS清洗;所述NaOH溶液浓度为0.1M,裂解温度为4℃。
本发明有益效果为:
本发明用于预测分化型甲状腺癌摄碘状态的类器官培养方法,通过特定的培养基及培养方法,得到的分化型甲状腺癌类器官、正常甲状腺类器官和甲状腺髓样癌类器官,用于分化型甲状腺癌术后摄碘能力预测,结果准确,将由其构建的分化型甲状腺癌术后摄碘能力的预测系统和预测方法用于实际临床,具备广阔的应用前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1 本发明所述培养条件下9例样本的类器官摄碘实验结果;
图2 病灶明显摄碘的影像图;A. 患者131I全身扫描图像提示胸部及下腹部存在摄碘病灶;B. 患者胸部CT提示肺部多发转移灶;C. 患者腹部CT提示骨盆转移灶;
图3 病灶轻度摄碘的影像图;A. 患者131I全身扫描图像提示胸部存在轻度摄碘病灶;B-D. 患者胸部CT提示肺部多发转移灶;
图4 病灶不摄碘的影像图;A. 患者131I全身扫描图像未发现摄碘病灶;B. 患者胸部CT提示右肺转移灶;
图5类器官光镜图;A. 实验组① ;B. 实验组② ;C. 实验组③ ;D. 实验组④ ;E. 实验组⑤ ;F. 实验组⑥ ;G. 实验组⑦ ;H. 实验组⑧;
图6类器官统计结果;
图7 实验组③培养条件下2例样本的类器官摄碘实验结果;
图8 实验组③培养条件下样本1的临床影像图;A. 患者131I全身扫描图像提示颈部及胸部存在摄碘病灶;B.患者颈部CT提示左侧颈部淋巴结转移灶;C-D. 患者胸部CT提示肺部多发转移灶;
图9 实验组③培养条件下样本2的临床影像图;A. 患者131I全身扫描图像提示颈部及胸部存在摄碘病灶;B.患者颈部CT提示左侧锁骨上区淋巴结转移灶;C. 患者胸部CT提示肺部多发转移灶。
具体实施方式
本申请具体实施方式中使用的原料、设备均为已知产品,其中N2、B27、EGF、FGF、HGF、Nicotinamide、N-acetylcysteine等都是商用的细胞培养基成分,均可通过购买市售产品获得。本发明所用的类器官增殖培养基中1:100 N2是指N2与DMEM/F12培养基的体积比为1:100,其他的B27、R-spondin、 Noggin、Wnt3a与之含义相同。
实施例1 本发明类器官培养
组织样本收集:分化型甲状腺癌组织、正常甲状腺组织和甲状腺髓样癌组织标本离体后30分钟内完成取样,取组织0.5×0.5×0.5cm大小,用生理盐水冲洗去除残留血液,放入组织保存液(HTK液)中,4℃保存,30min内送往实验室。
类器官培养:分别将分化型甲状腺癌组织、正常甲状腺组织和甲状腺髓样癌组织切碎至1mm*1mm*1mm大小,加入消化液(含 500 µg/ml Collagenase type XI和 200 µg/mlDnase-1的1% DMEM/F12溶液)中,37℃消化0.5-1小时。研磨,过滤,800rpm离心5min,去除上清液,若沉淀可见红色,则用红细胞裂解液常温处理2min,再次离心去上清液。加200-500ul(根据沉淀体积调整)Matrigel混匀,铺在24孔板中(每孔50ul)。待Matrigel凝固后,每孔加500ul类器官增殖培养基,即含N2(1:100),B27 (1:50),EGF 50ng/mL,FGF 100ng/mL,HGF50ng/mL,Nicotinamide 10mmol/L,N-acetylcysteine1.25mmol/L,Y-27632 10μmol/L,A83-01 5μmol/L,SB202190 5μmol/L,R-spondin(1:10), Noggin(1:10), Wnt3a(1:10),1%PS,1% Glutamax以及1% Hepes的DMEM/F12培养基,在37℃培养箱中培养2周,期间2-3天更换一次培养基,得分化型甲状腺癌原代类器官、正常甲状腺原代类器官和甲状腺髓样癌原代类器官。
分别取原代类器官,加消化液消化成单细胞,铺于细胞培养板中,每孔铺105细胞,加Matrigel和类器官增殖培养基按照原代类器官相同方法培养,得第2代类器官。
实施例2分化型甲状腺癌术后摄碘能力的预测系统
1)甲状腺相关类器官:实施例1制备的第2代的分化型甲状腺癌类器官、正常甲状腺类器官和甲状腺髓样癌类器官;
2)摄碘试验相关仪器和试剂:仪器包括细胞培养板,试剂包括Na131I溶液、PBS溶液和NaOH溶液;
3)甲状腺相关类器官摄取131I后放射性辐射数据的采集装置:伽马计数仪;
4)放射性辐射数据的分析装置。
实施例3预测分化型甲状腺癌术后摄碘能力
分别取实施例1培养的第2代类器官进行摄碘实验,即吸走培养液,加入预热至37摄氏度的Na131I溶液(配成1uCi/mL,每孔100uL),孵育60min后,吸走上清,用预热至37摄氏度的PBS清洗3遍,预冷至4摄氏度的0.1M NaOH溶液将细胞裂解,转移至测量管中,用伽马计数仪测量放射性计数。
分化型甲状腺癌类器官放射性计数大于等于150 CPM/105cells为轻度摄碘,放射性计数大于等于300 CPM/105cell为摄碘能力良好;正常甲状腺类器官放射性计数大于500CPM/105cells,甲状腺髓样癌类器官放射性计数小于50 CPM/105cells,摄碘能力预测结果准确。
以下通过试验例的方式进一步说明本发明的有益效果:
实验例1 本发明类器官对摄碘实验影响
一、方法
1、试验用类器官
按实施例1方法培养的来源于存在远处转移的初治分化型甲状腺癌患者或131I治疗后的复发分化型甲状腺癌患者的肿瘤原代类器官,共9例。
2、摄碘实验
将肿瘤原代类器官消化成单细胞后计数,取96孔细胞培养板,每孔铺105细胞,按照原代类器官相同方法培养,待细胞生长成均一的类器官(即第2代类器官)后进行摄碘实验,即吸走培养液,加入预热至37摄氏度的Na131I溶液(配成1uCi/mL,每孔100uL),孵育60min后,吸走上清,用预热至37摄氏度的PBS清洗3遍,预冷至4摄氏度的0.1M NaOH溶液将细胞裂解,转移至测量管中,用伽马计数仪测量放射性计数。
由于环境中存在一定剂量的本底辐射(约0~100CPM不等),为排除环境本底对结果解读的干扰,设置阳性及阴性对照组判断类器官摄碘状态。本方案设置以实施例1方法培养的第2代正常甲状腺类器官作为阳性对照、第2代甲状腺髓样癌类器官作为阴性对照,辅助摄碘实验结果解读,以期达到对分化型甲状腺癌类器官摄碘能力的准确预测。
3、结果
摄碘实验结果显示,阳性对照正常甲状腺类器官放射性计数大于500 CPM/105cells,阴性对照甲状腺髓样癌类器官放射性计数小于50 CPM/105cells,排除了环境本底对结果解读的干扰。
9例样本的类器官摄碘实验结果及代表性病例临床显像结果见图1~4。从结果得出:肿瘤类器官摄取131I放射性计数大于等于300 CPM/105cells的三例患者131I治疗剂量显像提示病灶明显摄碘(例:图2);肿瘤类器官摄取131I放射性计数大于等于150 CPM/105cells、小于300 CPM/105cells的两例患者131I治疗剂量显像提示病灶轻度摄碘(例:图3);肿瘤类器官摄取131I放射性计数小于150 CPM/105cells的四例患者131I治疗剂量显像提示病灶不摄碘(例:图4)。
实验结果说明:将本发明制备得到的分化型甲状腺癌类器官、正常甲状腺类器官和甲状腺髓样癌类器官,用于分化型甲状腺癌术后摄碘能力预测,结果准确,能精准识别分化型甲状腺癌患者病灶摄碘能力。
实验例2 本发明类器官制备研究
类器官对分化型甲状腺癌摄碘状态的影响是显著的,以下对不同培养基培养得到的分化型甲状腺癌类器官进行观察,并进行摄碘实验。
实验组① 按照实施例1的方法培养分化型甲状腺癌类器官;
实验组② 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有B27。
实验组③ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有N2。
实验组④ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有A8301。
实验组⑤ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有R-Spondin1。
实验组⑥ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有SB202190。
实验组⑦ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有FGF。
实验组⑧ 按照实施例1的方法培养分化型甲状腺癌类器官,区别在于所使用的培养基中不含有Y27632。
培养开始后3周在镜下统计每组类器官个数,光镜图及统计结果见图5、图6。如结果所示,相较实验组②~⑧,实验组①可显著增加分化型甲状腺癌类器官培养成功率。
取培养效率最高的实验组①与实验组③得到的分化型甲状腺癌第2代类器官进行摄碘实验。实验组①结果示例见图1-4,实验组③结果见图7-9。图8及图9所示患者碘-131全身显像提示患者体内病灶显著摄碘,而图7中患者肿瘤类器官无显著摄取,类器官摄碘实验结果与实际摄碘不符。综上认为仅按本发明中提供的完整培养基配方培养而得的类器官进行摄碘实验可准确预测临床摄碘状态。
Claims (10)
1.一种用于预测分化型甲状腺癌摄碘能力的类器官培养方法,其特征在于:它包括以下步骤:
取甲状腺组织,切碎,加消化液消化,研磨过滤,离心,取沉淀加Matrigel混匀,凝固后加类器官增殖培养基培养,即得;
所述类器官增殖培养基是含1:100 N2,1:50 B27,50ng/mL EGF,100ng/mL FGF,50ng/mL HGF, 10mmol/L Nicotinamide,1.25mmol/L N-acetylcysteine,10μmol/L Y-27632,5μmol/L A83-01,5μmol/L SB202190,1:10 R-spondin, 1:10 Noggin,1:10 Wnt3a,1% PS,1%Glutamax和 1% Hepes的DMEM/F12培养基。
2.根据权利要求1所述培养方法,其特征在于:所述组织切碎至1mm*1mm*1mm;所述消化液是含500 µg/ml Collagenase type XI和 200 µg/ml Dnase-1的1% DMEM/F12溶液;所述消化的温度37℃,时间0.5-1小时;所述离心的速度800rpm,时间5min;所述沉淀见红色,用红细胞裂解液20-25℃处理2min,800rpm离心5min,去上清液;所述培养的温度为37℃,时间2周。
3.一种用于预测分化型甲状腺癌术后摄碘能力的类器官,其特征在于:它是分化型甲状腺癌组织、正常甲状腺组织和甲状腺髓样癌组织按照权利要求1所述方法制备而成的类器官。
4.权利要求3所述类器官在制备分化型甲状腺癌术后摄碘能力的预测系统中的用途。
5.一种分化型甲状腺癌术后摄碘能力的预测系统,其特征在于:它包括:
1)甲状腺相关类器官;
所述甲状腺相关类器官为权利要求3所述类器官的第2代;
2)摄碘试验相关仪器和试剂;
3)甲状腺相关类器官摄取131I后放射性辐射数据的采集装置;
4)放射性辐射数据的分析装置。
6.根据权利要求5所述的预测系统,其特征在于:所述仪器包括细胞培养板;试剂包括Na131I溶液、PBS溶液和NaOH溶液;所述采集装置包括伽马计数仪。
7.根据权利要求5所述的预测系统,其特征在于:所述摄碘能力分为轻度摄碘和摄碘能力良好;所述轻度摄碘的分化型甲状腺癌类器官放射性计数大于等于150 CPM/105 cells;所述摄碘能力良好的分化型甲状腺癌类器官放射性计数大于等于300 CPM/105 cells;所述摄碘能力预测结果准确时正常甲状腺类器官放射性计数大于500 CPM/105 cells,甲状腺髓样癌放射性计数小于50 CPM/105 cells。
8.权利要求3所述类器官在预测分化型甲状腺癌术后摄碘能力中的用途。
9.一种预测分化型甲状腺癌术后摄碘能力的方法,其特征在于:它包括如下步骤:
分别取甲状腺相关类器官,加Na131I溶液孵育,除去上清,清洗后加NaOH溶液裂解细胞,采用伽马计数仪测量放射性计数;
所述甲状腺相关类器官为权利要求3所述类器官的第2代;
所述类器官中分化型甲状腺癌类器官放射性计数大于等于150 CPM/105 cells为轻度摄碘,放射性计数大于等于300 CPM/105 cell为摄碘能力良好;正常甲状腺类器官放射性计数大于500 CPM/105 cells,甲状腺髓样癌类器官放射性计数小于50 CPM/105 cells,摄碘能力预测结果准确。
10.根据权利要求9所述的方法,其特征在于:所述类器官在孔板中每孔加100uL Na131I溶液;所述Na131I溶液浓度为1uCi/mL,孵育温度为37℃;所述孵育的时间为60min;所述清洗是用37℃ PBS清洗;所述NaOH溶液浓度为0.1M,裂解温度为4℃。
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