Mitochondrial targeted catalase suppresses invasive breast cancer in mice.
Mitochondrial targeted catalase suppresses invasive breast cancer in mice.
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DOI：
10.1186/1471-2407-11-191
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发表时间：
2011-05-23
期刊：
影响因子：
3.8
通讯作者：
Ladiges W
中科院分区：
文献类型：
--
作者：
Goh J;Enns L;Fatemie S;Hopkins H;Morton J;Pettan-Brewer C;Ladiges W
浸润性乳腺癌的治疗失败率高得惊人，因为有效的靶点尚未确定。一个潜在的靶点是线粒体产生的活性氧（ROS），因为ROS的产生与底物代谢的变化和肿瘤和基质细胞中抗氧化酶的浓度降低以及转移潜力增加有关。将表达人过氧化氢酶基因（mCAT）的转基因小鼠与发展转移性乳腺癌的MMTV-PyMT转基因小鼠杂交。所有小鼠（33 mCAT阳性和23 mCAT阴性）在110日龄时终止，此时肿瘤进展良好。组织学评估肿瘤在肺中的侵袭性、增殖和转移灶。测定ROS水平和p38 MAPK活化状态。表达mCAT的PyMT小鼠具有12.5%的高组织学级别原发性肿瘤侵袭性，而没有mCAT的PyMT小鼠的发生率为62.5%。组织学分级与转移发生率相关，56%的PyMT小鼠mCAT阳性显示肺转移证据，而85.4%的PyMT小鼠mCAT阴性显示肺转移（p ≤ 0.05）。表达mCAT的PyMT肿瘤细胞具有较低的ROS水平，并且比野生型肿瘤细胞对过氧化氢诱导的氧化应激更具抗性，这表明mCAT具有淬灭细胞内ROS和随后的侵袭行为的潜力。表达mCAT的PyMT小鼠中的转移性肿瘤负荷为0.1 mm2/cm2肺组织，而表达野生型等位基因的PyMT小鼠中的肺组织为1.3 mm2/cm2（p ≤ 0.01），表明mCAT可在减轻远处器官部位的转移性肿瘤进展中发挥作用。mCAT在肺中的表达增加了对过氧化氢诱导的氧化应激的抵抗力，这与p38 MAPK的活化减少有关，表明ROS信号传导依赖于p38 MAPK的至少一些下游效应。靶向肿瘤细胞和肿瘤基质细胞的线粒体内的过氧化氢酶抑制ROS驱动的肿瘤进展和转移。因此，增加线粒体隔室的抗氧化能力可能是侵袭性乳腺癌的合理治疗方法。请参阅相关评论文章：www.example.com
Treatment of invasive breast cancer has an alarmingly high rate of failure because effective targets have not been identified. One potential target is mitochondrial generated reactive oxygen species (ROS) because ROS production has been associated with changes in substrate metabolism and lower concentration of anti-oxidant enzymes in tumor and stromal cells and increased metastatic potential. Transgenic mice expressing a human catalase gene (mCAT) were crossed with MMTV-PyMT transgenic mice that develop metastatic breast cancer. All mice (33 mCAT positive and 23 mCAT negative) were terminated at 110 days of age, when tumors were well advanced. Tumors were histologically assessed for invasiveness, proliferation and metastatic foci in the lungs. ROS levels and activation status of p38 MAPK were determined. PyMT mice expressing mCAT had a 12.5 per cent incidence of high histological grade primary tumor invasiveness compared to a 62.5 per cent incidence in PyMT mice without mCAT. The histological grade correlated with incidence of metastasis with 56 per cent of PyMT mice positive for mCAT showing evidence of pulmonary metastasis compared to 85.4 per cent of PyMT mice negative for mCAT with pulmonary metastasis (p ≤ 0.05). PyMT tumor cells expressing mCAT had lower ROS levels and were more resistant to hydrogen peroxide-induced oxidative stress than wild type tumor cells, suggesting that mCAT has the potential of quenching intracellular ROS and subsequent invasive behavior. The metastatic tumor burden in PyMT mice expressing mCAT was 0.1 mm2/cm2 of lung tissue compared with 1.3 mm2/cm2 of lung tissue in PyMT mice expressing the wild type allele (p ≤ 0.01), indicating that mCAT could play a role in mitigating metastatic tumor progression at a distant organ site. Expression of mCAT in the lungs increased resistance to hydrogen peroxide-induced oxidative stress that was associated with decreased activation of p38MAPK suggesting ROS signaling is dependent on p38MAPK for at least some of its downstream effects. Targeting catalase within mitochondria of tumor cells and tumor stromal cells suppresses ROS-driven tumor progression and metastasis. Therefore, increasing the antioxidant capacity of the mitochondrial compartment could be a rational therapeutic approach for invasive breast cancer. Please see related commentary article: http://www.biomedcentral.com/1741-7015/9/62
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