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TS/A

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维基百科，自由的百科全书

TS/A是一种具有中等细胞分化能力的小鼠乳腺癌细胞系，最初在1983年分离自一只二十个月大的雌性BALB/c小鼠的自发性肿瘤[1][2]。在1990年代，它被广泛用作转导细胞因子基因及其他具有免疫学意义的基因的受体细胞系，以生产诱导着抗肿瘤免疫反应的重组实验疫苗[3]。因为具有异质性、低免疫原性及低转移能力的特性而使其适合作为临床前模型，并且可以应用于研究肿瘤-宿主相互作用和基因治疗方法等。

特征

TS/A细胞具有三倍体的核型[4]，并且在270位密码子的位置带有已突变的p53蛋白[5]，而大约三分之一的TS/A细胞均会表达癌症干细胞标记物Sca-1（英语：Sca-1）[6]，有研究发现Sca-1的表达几乎为阴性的TS/A细胞能被干扰素-γ诱导[7]，使其也能够表达Sca-1。TS/A细胞表达雌激素受体（英语：Estrogen receptor）[1]和内源性鼠类p185-erbB2产物[8]。

科研方面

当最初进行测试时，TS/A细胞并未赋予抵抗第二次攻击的保护[1]，故而显示出较低的免疫原性，此结论日后在其他研究中均得到证实[9]。TS/A细胞表达内源性逆转录病毒的Gp70env产物，其AH1免疫优势I类抗原决定了簇可以通过H-2Ld呈递被细胞毒性T细胞所识别[10]，而Gp70env抗原在大肠癌细胞系CT26等鼠类细胞系均存在着。在TS/A细胞中观察到Ld的下调[11]，原因可能是因为免疫编辑过程，逃避了宿主的免疫应答。TS/A细胞通过多种机制对宿主的免疫应答产生抑制作用，例如选择性丢失T细胞和B细胞中的STAT5a/b表达[12]，并且产生转化生长因子β1（英语：TGF beta 1）[13]、调节性T细胞的诱导[14]、对自然杀伤剂的抗性[15]，以及会产生破坏造血功能的集落刺激因子[16][17]，最终导致脾肿大及白细胞增多[18][19]。

当皮下注射到BALB/c小鼠体内时，TS/A细胞引起的局部肿瘤会迅速扩散到肺部。通过静脉内途径注射TS/A细胞后也可能观察到转移，因此可以比较转移过程早期和晚期的动力学[1][20]。在培养过程可以观察到TS/A细胞的异质性，因为它具有上皮样和成纤维细胞样形态，以及在培养物不依赖贴壁的生长方式[1][21]。从琼脂培养物中，TS/A细胞可以分离出两种类型的克隆细胞，既有致瘤性及转移性，但转移能力明显不同[21]。与具低转移性的成纤维细胞样克隆细胞相比，高转移性克隆出乎意料地普遍存在着。几种鼠类乳腺癌细胞系的基因表达谱都显示，TS/A-E1细胞（即高转移性的克隆细胞）与高度表达封闭蛋白的簇聚在一起[22]。有基因表达谱数据表明，封闭蛋白-3是高转移性克隆细胞中表达最高的基因，甚至比低转移性克隆表达高约90倍，而低转移性的克隆细胞则过度表达着NME4和神经细胞生长抑制因子等。

肿瘤-宿主相互作用

TS/A细胞诱导的肿瘤具有丰富且具异质性的浸润物，包括粒细胞及单核细胞/巨噬细胞亚群（subpopulations），而它们的相对比例在肿瘤的进展过程中发生变化[23]。这与已知的髓样细胞可塑性一致。几个亚群通过多种机制，有助于在TS/A肿瘤中，维持着能够促进肿瘤生长的微环境[24]。M2巨噬细胞是白细胞介素-10的大规模产生者，同时也是产生调节T细胞、辅助型T细胞、嗜酸性粒细胞和嗜碱性球的几种趋化因子的大规模产生者[24]。骨髓分离的抑制性细胞（英语：Myeloid-derived suppressor cell）（MDSC）是具异质性及未成熟的CD11b+/Gr-1+群体[25]，并且具有免疫抑制功能。目前已在TS/A模型系统中，研究了已极化的M2巨噬细胞及MDSC，以及规避促进肿瘤生长的策略，将已浸润的细胞转变为细胞分化程度更高的细胞。在TS/A模型中，M2肿瘤巨噬细胞的诱导是由CD20同源MS4A8A基因的表达所介导[26]。在TS/A肿瘤中，处于低氧性肿瘤区域的极化M2巨噬细胞数量更为丰富[23]，并且促进血管的生成。在TS/A肿瘤中，交替激活的M2肿瘤相关巨噬细胞表达着STAB1（英语：STAB1），其参与着将有害成分的吞噬过程，已经发现STAB1包含着细胞外基质骨结合素（英语：Osteonectin）（一种肿瘤抑制剂）的可溶成分。有研究指出Stabilin-1可能通过提高SPARC的清除率，从而在TS/A模型中发挥着促进肿瘤生长的作用[27]。

在TS/A肿瘤微环境中，其他非肿瘤细胞类型也可以起到促进肿瘤生长的作用，例如与肿瘤相关的成纤维细胞和脂肪细胞。通过肿瘤基质细胞共注射模型，在肿瘤相关的成纤维细胞中鉴定出新的候选肿瘤相关基因。微管蛋白酪氨酸连接酶（英语：Tubulin—tyrosine ligase）是研究最多的基因，其在肿瘤相关成纤维细胞中的表达下调，促进了TS/A肿瘤的生长[28]。TS/A细胞与脂肪细胞一起培养的话，将导致TS/A细胞中脂质含量的增加，以及肺部定植能力的提高[29]。从脂滴释放的游离脂肪酸是由三酸甘油脂水解酶（英语：Adipose triglyceride lipase）依赖性的脂解途径所介导的，而该途径则被认为是潜在的治疗靶标。肿瘤细胞与肿瘤相关脂肪细胞之间的代谢串扰，可能有利于上皮-间质转化（epithelial-mesenchymal transition），并且增加肿瘤的侵袭性。

TS/A细胞像其他肿瘤细胞系般分泌着外排体，然而在肿瘤生物学中起著相反的作用。外排体可能具有一定的免疫刺激作用。因为它们携带的肿瘤抗原可以转移到树突状细胞及细胞毒性T细胞[30]。然而外排体主要通过抑制着自然杀伤细胞的功能[31]及抑制骨髓树突状细胞进行分化[32]，从而发挥有效的免疫抑制性抗肿瘤免疫反应。经照射的TS/A细胞所释出的外排体显示出分子组成的改变，并且能够将双链DNA（dsDNA）转移到树突状细胞中，并且令共激分子（co-stimulatory molecules）的表达上调，以及引起STING（英语：Stimulator of interferon genes）依赖性的干扰素-1（英语：Interferon type I）激活[33]。

参考资料

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外部链接

检索自“https://zh.wikipedia.org/w/index.php?title=TS/A&oldid=74199896”