Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma.
Mesothelioma patient derived tumor xenografts with defined BAP1 mutations that mimic the molecular characteristics of human malignant mesothelioma.
复制标题
间皮瘤患者衍生出具有定义的BAP1突变的肿瘤异种移植物，这些突变模仿了人类恶性间皮瘤的分子特征。
DOI：
10.1186/s12885-015-1362-2
复制
发表时间：
2015-05-08
期刊：
影响因子：
3.8
通讯作者：
Hassan R
中科院分区：
文献类型：
--
作者：
Kalra N;Zhang J;Thomas A;Xi L;Cheung M;Talarchek J;Burkett S;Tsokos MG;Chen Y;Raffeld M;Miettinen M;Pastan I;Testa JR;Hassan R
恶性间皮瘤的新治疗方法的开发和评估一直很稀少，部分原因是缺乏合适的肿瘤模型。我们从5例晚期间皮瘤患者的胸水和腹水中建立了原代间皮瘤培养。电子显微镜和免疫组织化学(IHC)证实它们来自于间皮细胞。将细胞接种于裸鼠或SCID小鼠体内，用软琼脂集落形成法分析细胞的恶性潜能。采用突变分析、荧光原位杂交(FISH)分析和免疫组织化学(IHC)对原发患者肿瘤、早期传代细胞培养和患者来源的异种移植的分子图谱进行了评估。所有五种肿瘤的原代培养显示出与间皮瘤细胞一致的形态和免疫组化特征。在4个肿瘤中分别检测到BAP1和CDKN2A的突变。BAP1基因突变与BAP1蛋白表达缺失有关。三种细胞培养物均来源于BAP1突变的原发肿瘤，表现出锚定非依赖性生长，并在小鼠体内形成肿瘤，提示BAP1缺失可能促进体内肿瘤的生长。早期传代细胞培养和小鼠异种移植瘤都含有BAP1突变和CDKN2A缺失，与相应的原发患者肿瘤中发现的相同。我们建立的间皮瘤患者来源的具有与患者肿瘤相似的突变改变的异种移植瘤可用于临床前开发新的药物方案，并用于研究BAP1生物学在间皮瘤中的功能方面。本文的在线版本(doi：10.1186/s12885-0151362-2)包含补充材料，授权用户可以使用。
The development and evaluation of new therapeutic approaches for malignant mesothelioma has been sparse due, in part, to lack of suitable tumor models. We established primary mesothelioma cultures from pleural and ascitic fluids of five patients with advanced mesothelioma. Electron microscopy and immunohistochemistry (IHC) confirmed their mesothelial origin. Patient derived xenografts were generated by injecting the cells in nude or SCID mice, and malignant potential of the cells was analyzed by soft agar colony assay. Molecular profiles of the primary patient tumors, early passage cell cultures, and patient derived xenografts were assessed using mutational analysis, fluorescence in situ hybridization (FISH) analysis and IHC. Primary cultures from all five tumors exhibited morphologic and IHC features consistent to those of mesothelioma cells. Mutations of BAP1 and CDKN2A were each detected in four tumors. BAP1 mutation was associated with the lack of expression of BAP1 protein. Three cell cultures, all of which were derived from BAP1 mutant primary tumors, exhibited anchorage independent growth and also formed tumors in mice, suggesting that BAP1 loss may enhance tumor growth in vivo. Both early passage cell cultures and mouse xenograft tumors harbored BAP1 mutations and CDKN2A deletions identical to those found in the corresponding primary patient tumors. The mesothelioma patient derived tumor xenografts with mutational alterations that mimic those observed in patient tumors which we established can be used for preclinical development of novel drug regimens and for studying the functional aspects of BAP1 biology in mesothelioma. The online version of this article (doi:10.1186/s12885-015-1362-2) contains supplementary material, which is available to authorized users.
登录
查看更多内容
BRCA1相关蛋白-1是一种需要去泛素化活性和核定位的肿瘤抑制剂。
影响因子：
11.2
作者：
Ventii KH;Devi NS;Friedrich KL;Chernova TA;Tighiouart M;Van Meir EG;Wilkinson KD
通讯作者：
Wilkinson KD
影响因子：
20.3
作者：
Xi, Liqiang;Arons, Evgeny;Kreitman, Robert J.
通讯作者：
Kreitman, Robert J.
影响因子：
2.8
作者：
Mohamedali, Azim;Lea, Nicholas C.;Kocher, Hemant M.
通讯作者：
Kocher, Hemant M.
影响因子：
4.8
作者：
Parson, W;Kirchebner, R;Kofler, R
通讯作者：
Kofler, R
影响因子：
24.3
作者：
Orengo, AM;Procopio, A;Mutti, L
通讯作者：
Mutti, L