我要获得自由——肿瘤微环境和转移 (肿瘤微环境系列4)

“几乎没有癌症患者死于原发性肿瘤;几乎所有的癌症患者都是死于肿瘤的转移”

对病人、医生和研究人员来说,癌症的转移是一个巨大的挑战。

没有人是孤岛,肿瘤细胞也是如此。在我们的“微环境”系列文章中,先前的文章讨论了肿瘤周围的细胞和结构对其生存是如何的重要

在这篇文章中,我们将探索肿瘤如何在这些细胞中释放,以挣脱并扩散到身体的其他部位。

癌症扩散(或转移)的过程对于癌症患者和他们的医生来说是一个巨大的问题;大多数死于癌症的原因是疾病在身体周围扩散。因此,了解癌症细胞如何从原发肿瘤的局限中挣脱出来,并在身体周围活动,这对科学家来说是一个至关重要的问题。

肿瘤转移对患者、医生和研究者是巨大的挑战

我们学得越多,我们就越意识到发展转移的能力对于肿瘤来说不是一件容易的事情——他们在没有帮助的情况下是不会成功的。所以,在这里,我们将了解他们健康的邻居是如何打发他们的。

我得到了朋友们的一点帮助

肿瘤和周围环境之间的持续对话,积极地支配着它的行为,并帮助它发展和繁荣。偷听这些流言蜚语告诉我们,微环境对于帮助肿瘤动员其军队的“迷你我”到达全身至关重要。

微环境并不总是坏影响;在肿瘤发展的早期阶段,它可以减缓肿瘤的生长——有效地使癌细胞分子敲击关节并让它们表现得很好。但随着时间的推移,这些信号会被更大的声音淹没,持续的声音会哄骗并刺激肿瘤细胞撞击道路。

改变什么呢?几乎一切。就像我们已经看到的那样,炎症的背景会导致癌症细胞逐渐累积遗传错误,从而导致从他们的床上分离出来的基因缺陷。当血管生成通过血流提供一条逃生通道时,微环境就会远离阻止转移,并积极地促进癌细胞在身体周围的扩散。

基质,将旅行

基质——也被称为“结缔组织”——为组织和器官提供结构支持,但科学家们开始意识到它在肿瘤的发展中也起着关键作用。基质细胞被共同选择启动血管生成和炎症,但它们仍留在周围,以帮助癌细胞摆脱它们的邻居,并在肿瘤的肿块中蠕动。

它们还会溶解像果冻一样的强力胶(称为细胞外基质或ECM),它们可以一起组织细胞,为肿瘤细胞的逃逸铺平道路。

接下来的幸存者将面临跨越血管壁的挑战——这一过程被称为血管内渗。为了做到这一点,他们需要一种被称为蛋白酶的化学物质,它通过分子砌体形成血管壁。虽然癌细胞本身会产生大量的蛋白酶,但被称为巨噬细胞的白细胞也提供了充足的物质来源——最终让逃逸者进入血管并沿着血液循环。

我们需要一艘更大的船。

血液是转移癌细胞的危险场所。图片来自Wikimedia Commons。

血液对肿瘤细胞来说是一个特别危险的环境——它充满了巡逻的免疫细胞和血液流动的强力,在血液循环中“冲浪”可能是致命的。

癌细胞在“血流”中冲浪随时有死亡的风险

但帮助就在眼前。血小板聚集在这个场景中,受到了由该细胞产生的化学物质的引诱。它们的作用是聚集在一起形成不溶性物质——在受伤后需要血凝块时特别有用的技能。但在这里,它们在肿瘤细胞周围形成一个保护屏障,保护它免受剪切或免疫攻击,并帮助它安全地穿过危险的水域。

给我庇护

在某一时刻,肿瘤细胞到达一个次级部位——通常是肺部、大脑或骨骼。

但是,旅途还远未结束,因为这个疲惫的旅行者迷失了方向,远离家乡,肿瘤细胞面临着在他们挨饿和死亡之前建立营地的挑战。

正如你所预料的那样,在这个陌生的环境中生存依赖于快速结交新朋友——而这个“转移龛metastatic niche”将成为本系列下一篇文章的主题。

没有足够高的山

对于世界各地的病人来说,转移的开始是他们疾病演变的一个转折点——这是外科手术刀不再是治疗的重点转择点,而且成功的治疗变得非常困难。每年都有成千上万的男人、女人和孩子被告知他们的选择已经用尽了,而且已经没有更多的治疗选择了。

但我们不会放弃。即使是对人类历史的不经意一瞥,也显示了我们处理看似无法克服的身体和智力挑战的无穷能力——我们在冰河时代幸存下来,我们已经分裂了原子,我们已经登上了月球,回到了地球。对于癌症研究人员和患者来说,转移可能是我们面临的最大挑战。

但是,多亏了我们的朋友们的一点点帮助,以及我们的科学家们在全国上下的创造力,我们将到达那里。

进一步的阅读

Joyce J.A. & Pollard J.W.(2008)。转移的微环境调节Microenvironmental regulation of metastasis,癌症自然评论Natural Reviews Cancer,9(4)239-252。DOI:10.1038 / nrc2618

参考文献

I want to break free – the microenvironment and metastasis

Category: Science blog February 11, 2013 Safia DanoviComments are closed

This entry is part 4 of 5 in the series Microenvironment

Cancer spread is a huge challenge for patients, doctors and researchers.

Cancer spread is a huge challenge for patients, doctors and researchers.

No man is an island, and the same can be said of tumour cells. Previous posts in our ‘microenvironment’ series have discussed how the cells and structures around a tumour – known collectively as its microenvironment – are crucial to its survival.

In this article we explore how tumours draft in these surrounding cells to break free and spread to other parts of the body.

This process of cancer spread (or metastasis) is a huge problem for cancer patients and their doctors; most deaths from cancer are caused by the disease spreading around the body. So understanding how cancer cells break free from the confines of the primary tumour and move around the body is a crucial question for scientists.

And the more we learn, the more we realise that developing the ability to spread is no easy feat for tumours – they wouldn’t get anywhere without a helping hand. So here, we’ll learn about how their healthy neighbours send them on their way.

I get by with a little help from my friends

The constant chatter between a tumour and its surroundings actively dictates its behaviour and helps it develop and flourish. And eavesdropping on this gossip has taught us that the microenvironment is crucial for helping a tumour mobilise its army of ‘mini me’s throughout the body.

The microenvironment isn’t always a bad influence; at early stages of tumour development, it can slow down a tumour’s growth – effectively giving cancer cells a molecular rap on the knuckles and telling them to play nice. But as time passes these signals are drowned out by much louder, persistent voices coaxing and goading tumour cells to hit the road.

So what changes? Almost everything. As we’ve already seen, a smouldering backdrop of inflammation causes cancer cells to gradually accumulate the genetic faults needed to cut loose from their bedfellows. And as angiogenesis takes hold and provides an escape route by way of the bloodstream, the microenvironment moves away from blocking metastasis and actively encourages the spread of cancer cells around the body.

Have stroma, will travel

The stroma – also known as ‘connective tissue’ – provides structural support to tissues and organs, but scientists are beginning to realise that it also plays a key role in tumour development. Stromal cells are co-opted to kick-start angiogenesis and inflammation, but they stick around to help cancer cells wriggle free from their neighbours and shimmy their way through the tumour mass.

They also dissolve the jelly-like superglue (called the extracellular matrix or the ECM) holding tissues together – clearing the path for tumour cells ready to escape.

Escapees next face the challenge of crossing blood vessel walls – a process called intravasation. To do this, they need chemicals called proteases, which chomp through the molecular masonry forming blood vessel walls. Although cancer cells make plenty of proteases themselves, white blood cells called macrophages also provide ample sources of the stuff – finally allowing the runaway to enter the blood vessel and set sail along the bloodstream.

We’re going to need a bigger boat

800px-Playboating3

The bloodstream is a risky place for metastasising cancer cells. Image from <a href=”https://commons.wikimedia.org/wiki/File:Playboating3.JPG” target=”_blank”>Wikimedia Commons</a>

The bloodstream is a particularly dangerous environment for tumour cells – it’s teeming with patrolling immune cells and the brute force of blood rushing though the circulation can be lethal.

But help is at hand. Platelets rush to the scene, lured in by chemicals produced by the flailing cell. They work by clumping together to form an insoluble mass – a particularly useful skill when a blood clot is needed following injury. But here, they form a protective shield around the tumour cell, guarding it against shearing or immune attack and helping it navigate safely through the dangerous waters.

Gimme shelter

At some point, the tumour cell arrives at a secondary site – often the lungs, brain or bone.

But the journey is far from over for this weary traveller – disorientated and far from home, tumour cells next face the challenge of setting up camp before they starve and perish.

And as you might expect, survival in this unfamiliar setting depends on making new friends very quickly – and this ‘metastatic niche’ will be the subject of our next post in this series.

No mountain high enough

For patients all over the world, the onset of metastasis is a game-changing moment in the evolution of their disease – it’s the point where the surgeon’s scalpel is no longer a cure, and successful treatment becomes extremely difficult. And each year, it’s when thousands of men, women and children are told their options have run out, and that little more can be done.

But we’re not giving up. Even a casual glance through human history shows our endless capacity to tackle seemingly insurmountable physical and intellectual challenges – we’ve survived the ice age, we’ve split the atom and we’ve been to the moon and back. For cancer researchers and patients, metastasis is possibly our biggest challenge.

But thanks to a little help from our friends – and the ingenuity of our scientists up and down the country, we will get there.

Further reading

Joyce J.A. & Pollard J.W. (2008). Microenvironmental regulation of metastasis, Nature Reviews Cancer, 9 (4) 239-252. DOI: 10.1038/nrc2618