Department of Comparative Medicine University of Washington, Seattle, USA.
BMC Cancer. 2011 May 23;11:191. doi: 10.1186/1471-2407-11-191.
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.
由于尚未确定有效的治疗靶点，侵袭性乳腺癌的治疗失败率令人震惊。一个潜在的治疗靶点是线粒体产生的活性氧（ROS），因为 ROS 的产生与肿瘤和基质细胞中底物代谢的变化、抗氧化酶浓度的降低以及转移潜力的增加有关。
表达人过氧化氢酶基因（mCAT）的转基因小鼠与 MMTV-PyMT 转基因小鼠杂交，后者发展为转移性乳腺癌。所有小鼠（33 只 mCAT 阳性和 23 只 mCAT 阴性）在 110 天龄时肿瘤进展良好时终止。评估肿瘤的侵袭性、增殖和肺部转移灶。测定 ROS 水平和 p38MAPK 的激活状态。
与未表达 mCAT 的 PyMT 小鼠相比，表达 mCAT 的 PyMT 小鼠原发性肿瘤侵袭性高组织学分级的发生率为 12.5%，而 PyMT 小鼠无 mCAT 的发生率为 62.5%。组织学分级与转移发生率相关，56%的 mCAT 阳性 PyMT 小鼠有肺转移证据，而 85.4%的 mCAT 阴性 PyMT 小鼠有肺转移（p≤0.05）。表达 mCAT 的 PyMT 肿瘤细胞的 ROS 水平较低，对过氧化氢诱导的氧化应激更具抵抗力，这表明 mCAT 有可能猝灭细胞内 ROS 并随后表现出侵袭行为。表达 mCAT 的 PyMT 小鼠的转移性肿瘤负担为 0.1mm2/cm2 肺组织，而表达野生型等位基因的 PyMT 小鼠为 1.3mm2/cm2 肺组织（p≤0.01），这表明 mCAT 可能在减轻远处器官部位转移肿瘤进展方面发挥作用。mCAT 在肺部的表达增加了对过氧化氢诱导的氧化应激的抵抗力，与 p38MAPK 的激活减少有关，这表明 ROS 信号依赖于 p38MAPK 来发挥其至少部分下游作用。
靶向肿瘤细胞和肿瘤基质细胞线粒体中的过氧化氢酶可抑制 ROS 驱动的肿瘤进展和转移。因此，增加线粒体区室的抗氧化能力可能是侵袭性乳腺癌的合理治疗方法。
