英国研究人员揭示了癌细胞如何处理遗传混乱

    根据今天发表在《癌症细胞》和《癌症探索》上的两篇新报道，科学家已经发现肿瘤如何能够生长，尽管染色体的数量和组织严重损环（DNA的存储单元）。

Charles Swanton教授说：“我们希望对机制的了解将会允许我们限制抗药性和改进癌症治疗的有效性”。

如果它们的基因中存在不能修复的错误，健康细胞被设定为自毁，但癌细胞可以随着这些异常行为继续生长。随着时间推移，进一步的遗传变化允许它们保持生长，扩散和变得对治疗有抗性。

但是这种基因混乱是可以被利用的，就如很多的基因重组一样也会推动癌细胞进入癌细胞死亡。

这个研究是由Francis Crick 研究院的科学家，Charles Swanton教授领导的，是英国癌症研究院部分资助的，现在已经发现癌症细胞在混乱中生存和生长的两种办法。

在一个研究中，研究人员发现具有异常数量的染色体的肠癌细胞在BCL9L基因中具有较高数量的缺陷。

他们发现在正常的细胞中，BCL9L帮助激活一种叫做半胱天冬酶-2的蛋白质以应对异常数量的染色体，引发自毁程序。

但是科学家发现通过使用各种技术使BCL9L基因钝化，

 具有不均匀数量的染色体的细胞不能够激活半胱天冬酶-2并且继续正常生长。

 这揭示了BCL9L的错误允许肠癌细胞处理异常数量的染色体，所以他们可以继续茁壮成长和进化。癌细胞通常在分裂的时候发生错误，导致不正确的染色体数量传递到子细胞。在这种情况下，癌细胞可以有一定数量的存活，在太多错误导致他们死亡之前有一个很好的平衡。

个研究揭示了癌细胞如何在这个阶段避免边缘。科学家发现错误在叫做APC/C的内部机械中，帮助癌细胞减慢分裂的过程，允许他们避免造成更多数量的错误在分发染色体给子细胞时。这就帮助癌症在肿瘤细胞之间建立基因的多样化。

 当研究人员在癌症细胞中把机械恢复到全速时，在他们分裂的时候他们会产生更多的基因错误-终意味着他们不能在染色体的混乱中生存下来。

伦敦Francis Crick 研究院的主要研究者，由英国癌症研究院部分资助的Charles Swanton教授说：“癌症的发展和进展是由不稳定的基因组推动的。它可以导致细胞之间的高度多样性，影响治疗工作和耐药性。如果癌细胞能够应对其DNA的大规模改变，那么它就可以获得帮助其生长，扩散和生存治疗的优势。到目前为止，我们很少知道这些癌细胞如何保持生长和进化。

   “我们希望对机制的了解将会允许我们限制抗药性和改进癌症治疗的有效性。”

病人的肿瘤细胞含有不正确染色体数量具有较差的生存率，因为这可导致致癌的症进展和耐药性。

英国癌症研究院首席科学家Karen Vousden教授说：“这两项研究揭示了癌细胞如何能够通过基因组成生存，从而导致正常细胞的死亡。潜在的令人兴奋的新方法是通过利用位于某些癌症核心的遗传混乱，打开靶向癌细胞的大门。”

Researchers reveal how cancer cells cope with genetic chaos

   Scientists have uncovered how tumours are able to grow despite significant damage to the structure and number of their chromosomes - the storage units of DNA - according to two new studies published in Cancer Cell and Cancer Discovery today.

"We hope that understanding these mechanisms will allow us to limit drug resistance and improve the efficacy of cancer therapies.” - Professor Charles Swanton

     Healthy cells are programmed to self-destruct if there are mistakes in their genes that can’t be fixed, but cancer cells can carry on growing with these abnormalities. Over time, further genetic changes allow them to keep growing, spread, and become resistant to treatment.

    But this genetic chaos can be exploited, as too much genetic reassortment will push cancer cells into cancer cell death too.

Led by Professor Charles Swanton, the Francis Crick Institute scientists, part-funded by Cancer Research UK, have now found two ways that cancer cells are able to survive and grow with this chaos.

In one study,the researchers found that bowel cancer cells with an abnormal number of chromosomes had a higher number of faults in the BCL9L gene.

They revealed that in normal cells, BCL9L helps activate a protein called caspase-2 in response to an abnormal number of chromosomes, triggering a self-destruct sequence.

But the scientists found that by inactivating the BCL9L gene, using various techniques, cells with an uneven number of chromosomes did not activate caspase-2 and continued growing normally.

    This suggests that the faults in BCL9L allow bowel cancer cells to cope with an abnormal number of chromosomes, so they can continue to thrive and evolve.

Cancer cells often make errors when dividing, leading to the incorrect number of chromosomes being passed on to daughter cells. While cancer cells can survive a certain amount of this, there is a fine balance before too many errors cause them to die.

    The second study reveals how cancer cells avoid tipping over the edge.Scientists found that faults in the internal machinery, known as APC/C, helps cancer cells to slow down the division process, allowing them to avoid making an excessive number of mistakes when distributing chromosomes to daughter cells. This helps the cancer build up genetic diversity between cells within the tumour.  

But when the researchers restored the machinery back to full speed in cancer cells they made more genetic errors as they divided – ultimately meaning that they could no longer survive the chaos in their chromosomes.

    Professor Charles Swanton, lead researcher based at the Francis Crick Institute in London and part-funded by Cancer Research UK, said: “The development and progression of cancer is fuelled by an unstable genome. It can cause a high degree of diversity between cells, influencing how well treatments work and drug resistance. If a cancer cell can cope with large scale changes to its DNA then it might gain an advantage that helps it to grow, spread and survive treatment. Until now, we knew very little about how these cancer cells kept growing and evolving.

   “We hope that understanding these mechanisms will allow us to limit drug resistance and improve the efficacy of cancer therapies.” 

Patients whose tumour cells contain an incorrect number of chromosomes have worse survival as this can lead to cancer evolution and drug resistance.

Professor Karen Vousden, Cancer Research UK’s chief scientist, said: “These two studies reveal more about how cancer cells are able to survive with a genetic makeup that would lead to the death of normal cells. This opens the door to potentially exciting new ways to target cancer cells – by exploiting the genetic chaos that lies at the heart of some cancers.”

媒体链接：英国研究人员揭示了癌细胞如何处理遗传混乱