了解肿瘤的“根”-肿瘤的血管生成 (肿瘤微环境系列2)

植物根系-血管是肿瘤的根 

图片来源:维基共

在本系列的第一篇文章中，我们解释了“邻居”或“微环境”如何影响癌症的生长和传播。

在下一篇文章中，我们将研究血管是如何在肿瘤生成并滋养肿瘤的。

血管生成

正如我们之前说过的，肿瘤可以被认为是身体里的一个“流氓器官”——不是对我们有用的，而是和其他器官有同样要求的。这包括血管网(血管网)，为癌细胞提供氧气和营养，并清除废物。而且，在癌症的情况下，使它能够存活、生长和传播到身体各处。

但是，当我们在子宫中发育时，血液供应给我们健康的组织提供了营养，一个肿瘤必须从附近的血管中找到自己的血液供应——这一过程被称为血管生成。

因为血管生成是癌症发展和扩散的基础，这是全世界癌症研究人员的一个激动人心的焦点。

找到问题的根源。

癌症有点像花园里的杂草——它们看起来像它们的邻居，但却占据了空间，与其他植物竞争，如果不加以控制，它们就有可能在整个花园中引发骚乱。

正如所有优秀的园丁所知道的，清除杂草的最好方法就是摧毁它们的根。如果不这样做，他们就会重新开始成长。

同样的，血管是肿瘤的根，喂养它，让它生长得更大。因此，针对这些根系和切断血液供应，应该是治疗癌症的好方法。这正是许多肿瘤血管生成领域的研究人员正在尝试做的事情。

针对肿瘤血管

瞄准血管来治疗癌症的想法是基于这样的发现:大多数成年人的血管都是静止的——换句话说，他们已经完成了所有的生长，然后停止了。

但也有一些例外。每个月，新的血管在女性的子宫中生长。每一次伤口愈合，新的血管就会在这个过程中恢复。但是(至少在理论上)针对新的血管生长的治疗应该是相对没有副作用的，因为它们的设计目的是针对肿瘤中生长的血管，而不是健康组织中静止的血管。

而且，肿瘤内血管的组成部分并不是真正的癌变——它们是健康的细胞，被癌症所劫持，去做他们通常不会做的事情。这意味着它们不太可能对治疗产生耐药性，因为它们不能像癌细胞那样变异和进化。所以，至少从理论上来说，这似乎是另一个加分点。

一些靶向肿瘤血管的药物已经被开发出来，包括“第一代”的治疗方法，如贝伐单抗(Avastin)，它阻断了一种叫做VEGF的分子，它是由肿瘤大量产生的，从而引发血管生成。

不幸的是，bevacizumab并没有在癌症患者身上显示出令人印象深刻的结果，这可能是早期实验室研究的结果(尽管与其他化疗药物联合使用效果更好)。而且这些类型的药物并没有像研究人员所希望的那么少的副作用。

自从VEGF被发现以来的30年里，许多癌症研究的英国科学家们已经对我们越来越多的了解它是如何和其他许多分子在血管生成中起着重要作用作出了贡献。因此，与其只专注于VEGF，其他的分子信使也可以同时瞄准，以避免耐药性和增加药物的效力。“第二代/第三代”抗血管生成疗法，如舒尼替尼(Sutent)和索拉非尼(Nexavar)已经进入临床，但研究人员仍在研究如何最好地使用它们。

因此，虽然阻断血管生长的想法一度看似简单，但事实证明并非如此简单。但是为什么呢?

肿瘤血管有什么特别之处?

研究人员现在认为，锁定肿瘤血管的关键在于了解什么使它们与健康的不同。虽然组成肿瘤血管的细胞本身是很正常的(因为它们的基因信息并没有像癌细胞那样被破坏)，但是整个血管却非常混乱。

有两种主要的细胞组成了小血管(被称为毛细血管或微血管)在肿瘤中发现:血管内皮细胞和周细胞，它们在外部支持它们。

在健康的毛细血管中，这些细胞类型是相当有组织的。内皮细胞就像罗马方阵的护盾一样，周细胞在关键点上支持它们，有助于稳定结构。

但在肿瘤内部，毛细血管壁有很大的缺口。内皮细胞可以随意进出，有时，周细胞不会出现帮助，有时甚至癌症细胞也会参与其中，假装是内皮细胞。这些管子的尺寸不规则，杂乱无章，扭曲扭曲，而不是像健康的毛细血管那样整齐排列。

这使得一个肿瘤的血管非常的渗漏和低效，导致它们释放出信号，从而驱动更多的血管生长，从而在恶性循环中滋养生长中的肿瘤。

意想不到的效果

为了尝试了解抗血管生成药物的令人失望的结果，科学家们仔细观察了治疗后肿瘤内部血管发生的变化。他们的发现出乎意料(尽管我们的研究人员艾伦·勒和库尔特·赫尔曼曾预测，这种情况可能会发生在20世纪70年代)。抗血管生成药物非但没有破坏肿瘤血管，反而似乎使这些奇怪的、无序的毛细血管变得更加正常。

起初，人们认为这是对整个抗血管生成治疗概念的灾难——当然，如果治疗能使肿瘤血管更好地发挥作用，那么癌细胞就会生长并传播得更快。这与医生和他们的病人想要的完全相反!

但仔细观察后，这种“正常化效应”实际上似乎是一件好事——如果我们能在适当的时候抓住它的话。原因如下:

使肿瘤血管更好地向肿瘤输送营养物质和氧气，对某些癌症治疗有积极作用。例如，如果化疗与抗血管生成药物一起使用，更有效的血液流动意味着更多的化疗药物可以获得更多的癌细胞杀死它们。这就解释了为什么像贝伐单抗这样的药物在化疗时似乎效果更好。

由于他们的血液供应紊乱，许多肿瘤的氧含量相对较低，这是一种被称为缺氧的现象，它似乎可以保护癌细胞不被放射治疗所破坏。稳定血管意味着更多的氧气进入肿瘤，增加体内的氧气含量。这有助于使放疗更有效。

随着肿瘤血管变得更加正常，它们似乎吸引了更多的支持周细胞，这有助于确保毛细血管对游离细胞的保护。一些研究人员已经表明，这可以降低癌症扩散(转移)的风险，当癌细胞进入血液并进入身体的另一个部位时就会发生转移。如果进入血管对癌细胞变得更加困难，这可能是一种预防癌症扩散的好方法。

把所有这些东西结合在一起，似乎抗血管生成药物可能不会像我们最初的想法(通过杀死血管和饥饿肿瘤)那样有用，相反，它们可能会使其他种类的治疗更加有效。

下一个研究重点在哪里?

世界各地的研究人员——包括那些由英国癌症研究机构资助的研究人员——现在正将这些新见解应用于寻找救命的癌症治疗方法。以下是我们在这方面的开创性工作的几个例子:

伦敦Barts癌症研究所的Kairbaan Hodivala-Dilke教授决定将基于血管生成的癌症治疗方法应用于临床。在她的实验室里，研究唐氏综合症——一种显然与癌症无关的现象——帮助我们更多地了解肿瘤和血管生长。

Adrian Harris教授领导牛津大学的一个团队。他们的前沿研究旨在揭示肿瘤如何吸引血液供应和低氧肿瘤环境的特征，将这些知识转化为改进的癌症疗法。哈里斯教授的研究有助于我们对著名的血管生长刺激因子VEGF的理解，以及另一种叫做deltaas 4 (DLL4)的分子信使。

他们的研究还发现了肿瘤的其他关键特征，如缺氧，并促使新的癌症治疗方法的发展。

David Tuveson教授直到最近还在英国剑桥研究院的癌症研究中心工作，他在理解血管在胰腺癌中的作用方面迈出了一大步。胰腺癌是一种致命的疾病，急需新的治疗手段。

在胰腺癌中，肿瘤细胞环境非常密集。血管的渗漏会导致肿瘤内部非常高的流体压力，使毛细血管崩溃，使血流几乎不存在。这意味着化疗药物(血液中携带的)根本无法进入肿瘤。

Tuveson教授的研究小组发现，解决这个问题的方法可能是使用药物的组合，其中包括分解肿瘤内致密堆积的药物。这有助于打开肿瘤血管，使化疗药物得以通过。

对未来的希望

研究抗血管增生疗法已经成为希望、失望和乐观情绪的过山车。

起初，它似乎是所有实体肿瘤的一个极有希望的目标，然后诊所的结果并没有达到预期。现在看来，他们可能真的很有效，但也许不是我们所期望的方式。只有进一步的研究才能告诉我们这些潜在的强有力的疗法是如何被用于治疗癌症的。

但是血管生长并不是我们看到的唯一有趣的发展领域:还有免疫系统和癌症扩散，所以要在肿瘤微环境中观察更多的信息。

Marianne Baker

Marianne Baker在英国癌症研究所资助的Barts癌症研究所攻读博士学位。

参考文献：

Getting to the root of tumour blood vessels

Category: Science blog January 18, 2013 Marianne BakerComments are closed

This entry is part 2 of 5 in the series Microenvironment

Plant roots

Blood vessels are the ‘roots’ of a tumour. Image source: Wikimedia Commons

In the first of this series we explained how the ‘neighbourhood’, or microenvironment, around a cancer affects how it grows and spreads.

In this next post we’re taking a look at how blood vessels grow into, and feed, a tumour.

Angiogenesis

As we’ve said before, a tumour can be thought of as a ‘rogue organ’ in the body – not one that is useful to us, but one that has the same requirements as any other. This includes a network of blood vessels (vasculature), supplying the cancer cells with oxygen and nutrients, and removing waste products. And, in the case of cancer, enabling it to survive, grow, and spread around the body.

But while the blood supply feeding our healthy tissues grows as we develop in the womb, a tumour has to ‘plumb in’ its own blood supply from nearby blood vessels – a process known as angiogenesis.

And because angiogenesis is so fundamental to how cancers grow and spread, it’s an exciting focus for cancer researchers all over the world.

Getting to the root of the problem

Cancers are a bit like weeds in the garden – they look like their neighbours but take up space and out-compete other plants, and have the potential to run riot over the entire garden if left uncontrolled.

As all good gardeners know, the best way to get rid of weeds for good is to destroy their roots. Fail to do this, and they’ll just start growing again.

In a similar way, blood vessels are the ‘roots’ of a tumour, feeding it and allowing it to grow bigger. Targeting these roots and cutting off the blood supply should therefore be a good approach for treating cancer.  And that’s exactly what many researchers in the field of tumour angiogenesis are trying to do.

Targeting tumour blood vessels

The idea of targeting blood vessels to treat cancer is based on the discovery that most blood vessels in adults are quiescent – in other words, they’ve done all the growing they need to and have then stopped.

But there are a couple of exceptions.  Every month, new blood vessels grow in a woman’s uterus during her menstrual cycle. And every time a cut heals, new vessels grow back during that process. But (in theory at least) treatments targeting new blood vessel growth should be relatively free of side-effects, because they’re designed to target the growing blood vessels in tumours and not the established quiescent vessels.

Also, the components of blood vessels within tumours aren’t actually cancerous themselves – they’re healthy cells that have been hijacked by a cancer to do things they usually wouldn’t. This means they should be less likely to develop resistance to treatments, because they’re less able to mutate and evolve in the same way as cancer cells. So – at least in theory – this seems like another plus point.

Some drugs that target tumour blood vessels have already been developed, including “first generation” therapies such as bevacizumab (Avastin), which blocks a molecule called VEGF that is produced in large amounts by tumours to provoke angiogenesis.

Unfortunately, bevacizumab didn’t show the impressive results in cancer patients that might have been expected from early lab studies (although it fared better in combination with other chemotherapy drugs). And these types of drugs haven’t had as few side effects as researchers had hoped.

In the 30 years since VEGF was discovered, many Cancer Research UK scientists have contributed to our growing understanding of how it – along with a multitude of other molecules – is important in angiogenesis. As a result, rather than focusing on VEGF alone, other molecular messengers can be targeted at the same time to try to avoid resistance and increase the drugs’ effectiveness. “Second/third generation” anti-angiogenic therapies such as sunitinib (Sutent) and sorafenib (Nexavar) have made it to the clinic, but researchers are still working out how best to use them.

So while the idea of blocking blood vessel growth once seemed straightforward, the reality turned out not to be quite so simple. But why?

What’s so special about tumour blood vessels?

Researchers now think that the key to targeting blood vessels in tumours lies in understanding what makes them different from healthy ones. While the cells that make up tumour blood vessels are themselves quite normal (in that their genetic information isn’t damaged like it is in cancer cells) the blood vessels as a whole are very messed up.

There are two main types of cells that make up the tiny blood vessels (called capillaries or microvessels) found in tumours: endothelial cells that line the walls of vessel tubes, and pericytes, which support them around the outside.

A Roman Phalanx

A Roman Phalanx – a little bit like blood vessels. Image source: Wikimedia Commons

In healthy capillaries, these cell types are quite well-organised. The endothelial cells fit together like the shields of a Roman phalanx and the pericytes support them at key points, helping to stabilise the structure.

But inside tumours, there are big gaps in the walls of the capillaries.  Endothelial cells come and go as they please, sometimes the pericytes don’t show up to help out, and sometimes even cancer cells get involved and pretend to be endothelial cells. The tubes have irregular sizes and are chaotically organised, twisting tortuously about instead of lining up neatly like healthy capillaries.

This makes a tumour’s blood vessels very leaky and inefficient, causing them to release signals that drive even more blood vessel growth to feed the growing tumour in a vicious cycle.

Unexpected effects

To try and understand the disappointing results of anti-angiogenic drugs, scientists took a closer look at what was happening to blood vessels inside tumours in response to the treatment. What they found was unexpected (although our researchers Alan Le Serve and Kurt Hellmann had actually predicted this might happen back in the 1970s). Instead of destroying tumour blood vessels, anti-angiogenic drugs seem to make the strange and disordered capillaries become more normal.

At first, people thought this spelled disaster for the whole concept of anti-angiogenic therapy – surely if the treatment makes the tumour blood vessels better at their job, the cancer will just grow and spread faster. This is the opposite of what doctors and their patients want!

But on closer inspection, this ‘normalisation effect’ actually looks like it might be a positive thing – if we can catch it at just the right time. Here’s why:

Making tumour blood vessels better at delivering nutrients and oxygen to the tumour can have positive effects on some cancer treatments. For example, if chemotherapy is given together with anti-angiogenics, the more efficient blood flow means more of the chemo drug can get to more of the cancer cells to kill them. This explains why drugs like bevacizumab seem to work better when given alongside chemo.

Because of their disorganised blood supply, many tumours have relatively low oxygen levels – a phenomenon known as hypoxia – which seems to protect cancer cells from being destroyed by radiotherapy. Stabilising blood vessels means that more oxygen gets into the tumour, raising oxygen levels inside it. This could help to make radiotherapy more effective.

As tumour blood vessels become more normal, they seem to attract more supporting pericytes, which help to secure capillaries against wandering cells. Some researchers have shown that this could reduce the risk of cancer spreading (metastasis), which happens when cancer cells enter the bloodstream and travel to another site in the body. If entering blood vessels becomes more difficult for cancer cells, this could be a good way to protect against cancer spread.

Combining all these things together, it seems that while anti-angiogenics might not be useful in the way we originally thought (by killing blood vessels and starving tumours), they might instead make the other kinds of treatments even more effective.

Where next?

Researchers all over the world – including those funded by Cancer Research UK – are now applying these new insights in the hunt for life-saving cancer treatments. Here are just a few examples of our pioneering work in this area:

Professor Kairbaan Hodivala-Dilke at the Barts Cancer Institute in London is determined to bring cancer therapies based on angiogenesis to the clinic. Work in her lab looking a Down’s syndrome – a phenomenon apparently unrelated to cancer – has helped us understand more about tumours and blood vessel growth.

Professor Adrian Harris heads a team at Oxford University. Their cutting-edge research aims to uncover more about how tumours attract a blood supply and the characteristics of low-oxygen tumour environments, turning this knowledge into improved cancer therapies. Professor Harris’ work has contributed to our current understanding of the famous blood vessel growth-stimulator VEGF, and another molecular messenger called delta-like 4 (DLL4). Their research has also picked apart other key features of tumours such as hypoxia and prompted the development of new cancer treatments.

Professor David Tuveson, who until recently was based at the Cancer Research UK Cambridge Research Institute, made a big step forward in understanding the role of blood vessels in pancreatic cancer – a  deadly disease for which new treatments are urgently needed.

In pancreatic cancer, the tumour cell environment is very dense. The leakiness of blood vessels leads to a very high fluid pressure within the tumour that collapses capillaries and makes blood flow almost non-existent. This means that chemotherapy drugs (which are carried in the bloodstream) simply can’t get into the tumour.

Professor Tuveson’s team found that the solution to this problem may lie in using a combination of drugs, including one that breaks down the dense packing within the tumour. This helps to open up the tumour blood vessels, allowing chemotherapy drugs to get through.

Hope for the future

Researching anti-angiogenic therapy has been somewhat of a rollercoaster of hope, disappointment and renewed optimism.

At first it seemed like a hugely promising target for all solid tumours, then the results from the clinic didn’t live up to expectations. Now it appears they could be really effective after all, but maybe not in the ways we expected. Only further research can tell us exactly how these potentially powerful therapies can be put to work to beat cancer.

But blood vessel growth isn’t the only area we’re seeing interesting developments in: there’s also the immune system, and cancer spread, so watch this space for more posts on the tumour microenvironment.

Marianne

Marianne Baker did her PhD at Barts Cancer Institute, funded by Cancer Research UK