2024, Vol. 44
引用本文
郭佩玉, 莫一青, 黄瑞雪. 类器官在放射治疗中应用的研究进展[J]. 中华放射医学与防护杂志, 2024, 44(1): 72-77, DOI: 10.3760/cma.j.cn112271-20230629-00216.
类器官在放射治疗中应用的研究进展
1. 中南大学湘雅公共卫生学院劳动与环境卫生系, 长沙 410078;
2. 杭州市拱墅区长庆潮鸣街道社区卫生服务中心, 杭州 310003
2. 杭州市拱墅区长庆潮鸣街道社区卫生服务中心, 杭州 310003
[摘要] 随着核能在军事、科研和医学各个领域的广泛应用, 放射医学已成为一门重要的学科。迄今为止, 放射医学的研究大多使用细胞模型和动物模型, 然而这两种模型都有其局限性, 类器官模型的出现填补了这些传统模型留下的空白。类器官是源自组织干细胞的3D体外培养系统, 类器官因其具有与原始组织相似的结构、功能和遗传特征而被广泛应用于放射医学、疾病研究、药物开发和癌症建模等领域。本综述按放射治疗部位介绍了各种类器官模型在放射治疗中的研究应用, 并对类器官模型目前的局限性及未来前景进行相关论述。
[关键词]
器官 类器官 模型 放射治疗 放射医学
Advances in research on the application of organoids in radiotherapy
1. Department of Occupational and Environmental Health, Xiangya School of Public Health, Central South University, Changsha 410078, China;
2. Hangzhou Gongshu District Changqing Chaoming Street Community Health Service Center, Hangzhou 310003, China
2. Hangzhou Gongshu District Changqing Chaoming Street Community Health Service Center, Hangzhou 310003, China
[Abstract] With the extensive applications of nuclear energy in the military, scientific research, and medical fields, radiological medicine has developed into a significant discipline. So far, studies of radiology have been conducted mostly using cell and animal models, both of which have limitations. Organoids, as 3D in vitro culture systems derived from tissue stem cells, have filled the gap left by these conventional models. They have been widely applied in review, disease research, drug development, and cancer modeling since their structures, functions, and genetic characteristics are akin to those of primary tissues. This review presents the applications of organoid models of various organ types in radiotherapy, as well as the limitations and prospects of organoids.
[Key words]
Organ Organoid Model Radiotherapy Radiological medicine
在过去的几十年中，癌症的预防、检测和治疗方面取得了重要的进展。然而，癌症仍然是全球最主要的健康问题，癌症患者仍然面临着生存质量低、复发率高等多种问题[1]。自使用放射治疗癌症以来，科学家们使用了许多模型来了解辐射损伤的分子机制，传统细胞模型一直是放射医学研究的基础，但2D培养的细胞系细胞类型单一，无法反映真实的体内环境[2]。类器官模型的出现填补了这种传统模型的漏洞。类器官是源自组织干细胞的3D体外培养系统[3]，与传统的2D培养相比，类器官因其具有与原始组织相似的结构、功能和遗传特征，而被广泛应用于疾病研究、药物开发和癌症建模等领域[4-5]。当前，类器官主要有两个分支，其一为正常类器官，常用于评估药物的毒理作用和药代动力学检测[6]：另一分支为肿瘤类器官，主要用于肿瘤发病机制、治疗反应和不良反应的研究[7-8]。
放射治疗的疗效主要受限于肿瘤干细胞的辐射抗性和转移能力，此外，还由该部位正常干细胞的再生能力决定[9]。因此，来源于干细胞的类器官模型对于研究辐射损伤的机制至关重要，其在确定治疗最佳方案中也发挥着重要的作用。按放射治疗的部位，本综述介绍各种类型类器官在放射医学中的研究进展，并对类器官模型目前的局限性及未来前景进行相关论述。
一、脑部肿瘤治疗脑是人类所知最为神秘、复杂的器官。目前，研究人员已经成功构建了大脑类器官模型[10]，并使用该模型研究脑发育过程中的一系列神经发育障碍性疾病[11-12]。
大量研究使用细胞模型揭示了脑部肿瘤干细胞的耐药机制[13]，但这些模型仍无法展示患者体内真实的肿瘤微环境。类器官模型问世后，研究人员使用患者来源的新鲜肿瘤组织样本成功构建了胶质母细胞瘤类器官模型[14]。有研究团队将患者来源的胶质瘤干细胞和正常的脑部干细胞共培养，发现共培养模型中胶质瘤类器官表现出更高的辐射抗性[15]；Oyefeso等[16]使用大脑类器官模型验证了低和中等剂量的质子射线对大脑的损伤作用，证明使用类器官模型来表征脑细胞辐射敏感性和辐射早期基因表达变化的有效性，这些研究足以说明类器官在脑部肿瘤放射治疗上的应用潜力。脑部类器官模型也被广泛用于临床新药物的开发。Jacob等[17]用10 Gy照射联合抗癌药物替莫唑胺(TMZ)刺激类器官以探究药物的作用机制；Pinto等[18]照射两种组织来源的胶质母细胞瘤类器官，发现具有GAP43表达的类器官线粒体的转移效率更高，且观察到类器官的肿瘤微管(TMs)和隧道纳米管(TNTs)之间形成了网络，从而提出了TMs和TNTs的交互作用会减弱放疗对胶质母细胞瘤的治疗作用的观点，为治疗药物的开发提供了新的靶点；Frisira等[19]发现γ射线和新型蛋白酶体抑制剂NPI-0052可以协同促进髓母细胞瘤类器官凋亡，从而提出了使用NPI-0052辅助放疗以治疗髓母细胞瘤的临床治疗新手段。
以上这些类器官模型的产生，不仅为研究脑部肿瘤的发育过程和放疗反应提供了极好的平台，也推动了更个性化的肿瘤治疗方法的产生[20]。
二、头颈部肿瘤治疗头颈癌是指起源于头部和颈部一系列肿瘤(除脑部和甲状腺外)[21]。目前，头颈癌患者主要是通过放疗或化疗进行治疗，但是头颈癌患者的生存情况并未明显改善。
为了提高放化疗的成功率，临床前预测模型起着关键作用。Driehuis等[22]使用患者来源的头颈部癌组织成功培养出头颈癌类器官，并使用放射和化疗药物处理类器官检测其反应，发现该类器官的反应和患者的临床反应相符；Karakasheva等[23]也发现初治患者活检组织来源的食管癌类器官可以真实地反映患者的临床反应；Millen等[24]比较了15名接受放疗的患者的类器官，结果显示放射敏感类器官与无复发生存期之间存在显著相关性。为进一步探究头颈部肿瘤放射敏感性的机制，Lucky等[25]用两种患者来源的异种移植物建立了首个低氧抗辐射鼻咽癌的体外类器官模型，发现缺氧类器官模型对辐射的敏感性比常氧类器官低1.4倍，为治疗低氧抗辐射鼻咽癌提供了一种低分割放射治疗的方法；Peng等[26]发现唾液腺衍生类器官在辐射暴露后衰老标志物表达增加，衰老细胞会促进辐射导致的唾液分泌减少，这为预防头颈部放疗所致的口干症提供了一种新的治疗策略。头颈部肿瘤类器官的研究有助于调整临床放射治疗方案及治疗放射所致的口干症，降低头颈部肿瘤的复发率和死亡率。
三、胸部肿瘤治疗胸部肿瘤包括肺癌、食管癌、乳腺癌等，其中肺癌是全世界发病率最高的癌症[27]。中国每年约有63.1万人死于肺癌[28]，乳腺癌也是我国女性发病率最高的恶性肿瘤[29]。
Hacker等[30]建立了乳腺癌类器官与巨噬细胞共培养体系，发现照射后巨噬细胞浸润到照射的类器官中，这与Rafat等[31]的研究结果一致；Falcone等[32]将乳腺癌等3种类器官模型暴露在辐射下，发现丝氨酸和甘氨酸缺乏组的类器官对射线更为敏感，提出了对临床放疗患者进行丝氨酸和甘氨酸饮食限制的治疗策略；Parsyan等[33]将一种新型的PLK4抑制剂CFI-400945与辐射联合刺激乳腺癌类器官发现二者具有协同抗癌作用，这可能为乳腺癌患者提供了一种新型组合治疗方式。不同于其他研究，Giuranno等[34]着眼于患者放疗所致的周围正常肺上皮损伤，他们发现NOTCH信号通路激活除了可以导致肿瘤细胞放射抵抗，还可以促进正常肺类器官在辐射后的增殖和存活，当前临床上广泛使用的小型NOTCH途径抑制剂联合放疗的治疗手段可能会影响正常组织的损伤修复，因此，应不断优化患者的治疗方案，以减小照射对正常组织的损伤。由此可见，患者来源的类器官模型被广泛应用于胸部肿瘤药物筛选、放疗机制研究和基因靶向精准治疗等多个方面。
四、腹部肿瘤治疗胃肠道类器官也是近年来发展最迅速和应用最为广泛的类器官模型。2009年，Sato等[35]通过提取小鼠肠道Lgr5(+)干细胞成功培养出“迷你肠道”类器官模型，随后研究人员从人类肠干细胞[36]以及胃肠道的不同位置(包括胃[37-38]，结肠[39-40]和食管[41])中建立了类器官。
胃癌是癌症相关死亡的第二大原因，也是全球第五大常见恶性肿瘤[42]。Yoshioka等[43]发现了一种新的干细胞标志物Bmi1，且在使用辐照、他莫希芬和乙酸诱导胃类器官损伤后也追踪到了Bmi1的表达，这种新的胃干细胞标志物的发现为开发新的胃癌疗法提供了重要框架；Wang等[44]使用胃癌类器官和胃癌细胞相结合进行研究，发现MCM6缺乏与放射增敏密切相关，并通过高通量筛选发现了一种新型MCM6抑制剂——紫癜苷C，为胃癌患者提供了一个新的治疗靶点；此外，胃癌类器官在化疗和靶向治疗药物筛选方面也发挥了重要的作用[45-46]。
我国结直肠癌的发病率呈现逐年上升的趋势，结直肠癌的死亡率在全部癌症中位列第三[47]。结直肠癌患者的治疗反应差异大，治疗效果不佳。近年来，肠道类器官模型在研究结直肠癌发生、发展及耐药机制方面发挥着越来越大的作用[48-49]。Ganesh等[50]建立了一个包含65个直肠癌类器官的生物库，结果表明离体和移植到小鼠直肠的类器官可以真实地反映患者对放疗的反应；Yao等[51]从80例患者中提取出了直肠癌类器官，并直接比较了类器官对辐射、5-氟尿嘧啶和伊立替康的实际反应，他们发现，这些癌症类器官能够以78%的灵敏度、92%的特异性和84%的准确率预测患者的临床结果；Chen等[52]发现抑制IDO1会增强肿瘤类器官的辐射治疗效果，且会明显降低放射对正常肠道的损伤作用，这也为结直肠癌患者的治疗提供了一个新的靶点；Bhanja等[53]使用肠类器官模型揭示了小分子抗肿瘤药物BCN057可减轻辐射诱导的肠道损伤并促进肠道干细胞修复；Martin等[54]发现肠类器官照射后大肠和小肠Lgr5(+)干细胞群的分布可以作为预测这些器官对辐射敏感性的标准。综上，类器官模型出现大大提高了临床上筛选抗癌药物的效率，进一步推动了精准医疗的发展[55]。
肝脏是人体最主要的“解毒器官”。放射性肝损伤是肝癌患者及其他腹部肿瘤患者的常见并发症之一[56]，目前，关于放射性肝损伤的了解大多是来自于临床上的病例对照研究[57]，体外研究的模型也仅限于类型单一和缺乏异质性的细胞模型[58-59]。近年来开发的类器官模型目前已经被广泛应用于遗传性肝病、药物性肝损伤、脂肪性肝炎等肝脏疾病的发病机制研究[60-63]。在未来，它也会是研究肝癌生物学特征和放射性肝损伤发病机制的理想临床前模型[64]。
五、类器官的局限性类器官在放射治疗及其他生物学领域中的作用越来越大，但仍存在以下局限性。虽然类器官是由多种细胞类型所构成的3D结构，但它仍无法真实地反映体内的微环境，不具有免疫细胞和相应的神经系统，而这些恰恰是组织发育和再生的关键因素[65]。研究表明，唾液腺的发育、再生及放射损伤修复过程中副交感神经的支配发挥着重要的作用[66-68]。寻找准确模拟组织中神经支配的类器官培养方法，对未来的研究非常重要[69-70]。器官-器官、肿瘤-器官和脉管系统的相互作用无法在类器官模型中实现[71]。组织的脉管系统对于营养物获得、组织再生、组织有效植入至关重要[72]。肿瘤脉管系统的反应，特别是血管生成，也被证明在放疗后肿瘤复发中起关键作用[73]。因此，研究人员使用了多种技术如生物打印、植入高度血管化的组织和与内皮细胞共培养等来设计富含血管的类器官，为研究放射疾病病理学提供了新的机会和模型[74-77]。类器官的培养有多种方案可供选择，但这些方案都具有培养周期长、培养技术复杂的特点[78]。研究人员往往需要数周到数月才能获得足够的类器官进行实验[79]，这也使类器官目前无法用来预测精准疗法中患者的反应，因为这种疗法往往要求在短时间治愈患者[80]。目前正在研发能同时兼顾类器官性能和优化培养时长的设计方案，以便在个性化药物实施之前快速准确地进行筛选[81]。
六、小结尽管类器官存在以上局限性，但类器官模型在放射生物学领域的前景仍然光明[82-83]，其在放射生物学中的地位也将随之上升。类器官不仅可用于观察放射的治疗效果，发现和验证辐射生物标志物，还可与CT等临床成像技术相结合探索肿瘤治疗的新疗法，更好地预测患者药物反应和个性化医疗，从而指导优化患者的治疗策略[84-85]。除此之外，类器官模型在制药行业的发展也十分乐观，通过可靠的校准和质量保证程序，类器官模型有望在临床中发挥调查癌症样本和发现新分子靶标的作用。
利益冲突 无
作者贡献声明 郭佩玉、莫一青负责文献调研和撰写论文；黄瑞雪负责设计论文框架、指导论文修改
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