关于癌细胞如何战胜缺氧的新发现~正常细胞缺氧会死亡，而癌细胞在缺氧条件下启动生存的级联反应
New clue to how cancer cells beat oxygen starvation
CHCHD4改变了低氧的生存机制
我们需要氧气才能生存。即使是我们身体最深处、最黑暗的部分的细胞也不能没有它。但是一些癌细胞会适应低氧水平的生存，而这些细胞最终会成为最难治疗的部分。
世界各地的实验室的科学家们正致力于揭开使细胞能够做到这一点的分子机制。他们希望通过开发能打破这些机制的治疗方法来战胜肿瘤。
这个月，我们的科学家们发现了一个重要的肿瘤细胞的氧感应机制，这可能是迈向治疗癌症的新方法的一个早期步骤。
氧传感器
随着肿瘤的快速生长和扩张，供应氧气的血管网络跟不上肿瘤生长的需要，导致一些细胞缺氧。这将杀死正常细胞，但是癌细胞已经进化到可以通过转换一种叫做低氧诱导因子(HIF)的蛋白质来克服这些条件，而这种蛋白质反过来又会改变细胞内的其他分子。
这种被称为“HIF反应”的级联反应，鼓励新的血管在肿瘤周围生长。它还能帮助肿瘤适应低氧环境，通过使用其他方法来产生能量。
一个细胞通过利用氧气来促进化学反应，在微小的“发电站”中产生能量，从而生长和生存。
众所周知，线粒体在“HIF”开关中扮演着重要的角色。
但研究人员仍不能确切地知道线粒体是如何参与的。因此，由Margaret Ashcroft领导的伦敦大学学院的一个团队开始着手调查。
打开了开关
这项研究发表在本月的临床研究杂志上，深入研究了线粒体的内部工作原理，发现氧气水平是由一种叫做CHCHD4的蛋白质来监测的。当氧含量低于临界水平时，这种蛋白质会激活HIF反应。
在实验室实验中，研究人员还改变了缺乏氧气的细胞中CHCHD4的水平。当CHCHD4完全被阻断时，它阻止了HIF在细胞中的作用，阻止癌细胞生长，更重要的是阻止了新血管的生长。
但是当大量的CHCHD4在缺氧的癌细胞中被激活时，大量的HIF被激活。这一过程启动了一系列的事件，使细胞能够在低氧环境中存活。
看起来CHCHD4在很多不同类型的癌症中都有它的激活作用。研究小组观察了236名乳腺癌患者的样本，发现CHCHD4的水平在最具侵袭性的样本中是最大的，而且来自较差的存活者。他们还发现，在胰腺癌和神经胶质瘤(一种脑肿瘤)患者的样本中，他们的CHCHD4水平升高。
再一次，在这些癌症中，他们发现CHCHD4的水平升高与恶性肿瘤和较低的存活率有关。
新的治疗机会?
正如我们上面所说的，尽管低氧水平的肿瘤细胞能够存活，但它们更有可能对治疗产生抗药性。先前的研究已经表明，以HIF反应为目标可以阻止肿瘤的生长和扩散，并提高阻止新血管生长的药物的效果(所谓的“抗血管生成素”)，因此这些结果有望在未来获得更有效的癌症治疗。
Ashcroft博士认为，这项工作开辟了一个新的领域，使我们对肿瘤细胞如何适应和在一个氧气稀少的环境中生存有了新的理解。
她告诉我们:“我们现在可以通过调整CHCHD4的作用来寻找新的方法来瞄准这一过程，希望能够研制出能够用于治疗那些难以治疗的癌症的新药。”
她的团队现在计划在进一步的研究中继续这项工作，我们将密切关注她在这个激动人心的领域的进展。
Reference
Yang, J. et al. (2012). Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression Journal of Clinical Investigation, 122 (2), 600-611 DOI: 10.1172/JCI58780
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New clue to how cancer cells beat oxygen starvation
Category: Science blog March 1, 2012 Simon ShearsComments are closed
CHCHD4 switches on a survival mechanism in low oxygen
We need oxygen to survive. Even the cells in the deepest, darkest parts of our body can’t live without it. But some cancer cells adapt to survive in very low oxygen levels, and these end up being some of the most difficult to treat.
Scientists in labs around the world are working to uncover the molecular machinery that allows cells to do this. And they hope to outsmart tumours by developing treatments that break these mechanisms.
This month our scientists discovered an important part of the oxygen-sensing machinery of tumour cells, which may be an early step towards a new way to treat cancer.
Oxygen sensor
As tumours rapidly grow and expand, the network of blood vessels bringing oxygen to their cells can’t keep up, leaving some cells starved of oxygen, or ‘hypoxic’. This would kill normal cells, but cancer cells have evolved to beat these conditions by switching on a protein called hypoxia-inducible factor (HIF), which in turn switches on other molecules inside the cell.
This cascade, called the HIF response, encourages new blood vessels to grow around and into the tumour. It also helps the tumour to adapt to hypoxic conditions by using alternative methods to produce energy.
A cell generates energy to grow and survive inside tiny ‘power stations’ called mitochondria, by using oxygen to fuel chemical reactions. And it’s been known for some time that mitochondria have an important role in flicking the ‘HIF’ switch.
But researchers were in the dark as to exactly how mitochondria are involved. So a team at University College London, led by Dr Margaret Ashcroft, set out to investigate.
Flicking the switch
The research, published in this month’s Journal of Clinical Investigation, delved into mitochondria’s inner workings and found that oxygen levels are monitored by a protein called CHCHD4. When oxygen levels fall below a critical level, this protein activates the HIF response.
In lab experiments, the researchers also varied the levels of CHCHD4 in cells starved of oxygen. When CHCHD4 was blocked entirely, it stopped the action of HIF in cells, stopping cancer cells from growing and – importantly – preventing the growth of new blood vessels.
But when too much CHCHD4 was switched on in oxygen-starved cancer cells, large amounts of HIF were activated. This kick started a sequence of events that allowed cells to survive in low oxygen.
And it seems CHCHD4 has this HIF-activating role in a number of different types of cancer. The team looked at samples from 236 breast cancer patients, and found that levels of CHCHD4 were greatest in samples that were most aggressive, and came from patients with poorer survival. They also found raised levels of CHCHD4 in samples from patients with pancreatic cancers and gliomas (a form of brain tumour).
Again, in these cancers, they found that increased levels of CHCHD4 were associated with more aggressive tumours and poorer survival.
New treatment opportunity?
As we said above, tumour cells that are able to thrive despite low oxygen levels are more likely to be resistant to treatment. Previous research has shown that targeting the HIF response can block tumour growth and spread, and improves the effect of drugs that halt the growth of new blood vessels (so-called ‘anti-angiogenics’), so these results could hold promise for more effective cancer treatments in the future.
Dr Ashcroft thinks the work opens a new area in our understanding of how tumour cells adapt and survive in an environment with little oxygen.
“We can now look at new ways of targeting this process by modulating the action of CHCHD4, hopefully leading to new drugs that could be used against those cancers that are difficult to treat,” she told us.
Her team now plans to continue this work in further studies, and we’ll be keeping an eager eye on her progress in this exciting field.
Reference
Yang, J. et al. (2012). Human CHCHD4 mitochondrial proteins regulate cellular oxygen consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression Journal of Clinical Investigation, 122 (2), 600-611 DOI: 10.1172/JCI58780
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