Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients.
Transfer of malignant trait to BRCA1 deficient human fibroblasts following exposure to serum of cancer patients.
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DOI：
10.1186/s13046-016-0360-9
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发表时间：
2016-05-14
期刊：
影响因子：
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通讯作者：
Arena GO
中科院分区：
文献类型：
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作者：
Hamam D;Abdouh M;Gao ZH;Arena V;Arena M;Arena GO
据报道，转移可能通过生物活性血液循环分子从原发肿瘤转移到远处器官而不仅仅是癌细胞的迁移而发生。我们在早期的研究中表明，将永生化的人胚肾细胞（HEK 293）暴露于癌症患者血清，由于恶性性状的水平转移而诱导其转化为未分化的癌症。在目前的工作中，我们测试的假设，即使是其他人类细胞，只要他们是缺乏一个单一的抑癌基因可能会发生恶性转化时，暴露于人类癌症血清。我们使用CRISPR/Cas9系统在人成纤维细胞中建立稳定的BRCA 1敲除（KO）。将BRCA 1-KO成纤维细胞暴露于癌症患者血清或健康患者血清2周。分析处理的细胞的细胞增殖和转化，以研究它们对癌症患者血清的致癌潜力的易感性，并确定它们假设的转化的可能机制。与野生型对照成纤维细胞相比，用癌症患者血清处理的BRCA 1-KO成纤维细胞显示出更高的增殖并经历恶性转化，野生型对照成纤维细胞不受暴露于癌症患者血清的影响。当用健康人血清处理BRCA 1-KO成纤维细胞时，未观察到恶性转化。对BRCA 1-KO成纤维细胞产生的肿瘤的组织学分析显示，它们是具有与供血者患者的癌症相关的表型特征的癌。有趣的是，与野生型成纤维细胞相比，BRCA 1-KO成纤维细胞显著更倾向于内化血清来源的外泌体。这表明抑癌基因也可能通过阻断癌症来源的外泌体的整合来保护细胞基因组的完整性。这些数据支持这样的假设，即任何携带单一抑癌基因突变的人类细胞都能够整合血液中携带的癌症因子，并经历完全的恶性转化。抑癌基因可能通过阻止这些突变因子在细胞内的整合来保护细胞基因组。本文的在线版本（doi：10.1186/s13046-016-0360-9）包含补充材料，可供授权用户使用。
It was reported that metastases might occur via transfer of biologically active blood circulating molecules from the primary tumor to distant organs rather than only migration of cancer cells. We showed in an earlier study that exposure of immortalized human embryonic kidney cells (HEK 293) to cancer patient sera, induce their transformation into undifferentiated cancers due to a horizontal transfer of malignant traits. In the present work, we tested the hypothesis that even other human cells as long as they are deficient for a single oncosuppressor gene might undergo malignant transformation when exposed to human cancer serum. We used the CRISPR/Cas9 system to establish a stable BRCA1 knockout (KO) in human fibroblasts. The BRCA1-KO fibroblasts were exposed to cancer patients’ sera or healthy patients’ sera for 2 weeks. Treated cells were analyzed for cell proliferation and transformation to study their susceptibility to the oncogenic potential of cancer patients’ sera and to determine the possible mechanisms underlying their hypothesized transformation. BRCA1-KO fibroblasts treated with cancer patients’ sera displayed higher proliferation and underwent malignant transformation as opposed to wild type control fibroblasts, which were not affected by exposure to cancer patients’ sera. The malignant transformation was not seen when BRCA1-KO fibroblasts were treated with healthy human sera. Histological analysis of tumors generated by BRCA1-KO fibroblasts showed that they were carcinomas with phenotypical characteristics related to the cancers of the blood donor patients. Interestingly, BRCA1-KO fibroblasts were significantly more prone to internalize serum-derived exosomes, when compared to wild type fibroblasts. This suggests that oncosuppressor genes might protect the integrity of the cell genome also by blocking integration of cancer-derived exosomes. These data support the hypothesis that any human cells carrying a single oncosuppressor mutation is capable of integrating cancer factors carried in the blood and undergo complete malignant transformation. Oncosuppressor genes might protect the cell genome by impeding the integration inside the cells of these mutating factors. The online version of this article (doi:10.1186/s13046-016-0360-9) contains supplementary material, which is available to authorized users.