Fred Hutchinson癌症研究中心/华盛顿大学: 癌症转移的科学-转移的方式和原因，以及如何阻止转移

Fred Hutchinson/University of Washington ：The Science of Cancer Spread

　

要点：

1.  癌细胞转移是一个非常低效的过程；大的肿瘤每天释放高达100万个的肿瘤细胞，进入血液，只有少数几个能存活定居下来；

2. 癌细胞的转移必须通过血液循环，通常需在血流中存留3天；（提示健康的血液有大量能识别和杀死癌细胞免疫细胞，就能歼灭血循环中的癌细胞）；

3. 癌细胞常常聚集在一起，成群结队的旅行-这是少数癌细胞能下血液这个非常不利的环境中存活下来的关键；

4. 癌细胞聚集（细胞-细胞连结）在一起依赖于黏蛋白，而黏蛋白依赖于钙离子的存在；镁离子是钙离子的天然拮抗物。这个关联是富含镁离子的蔬菜汁有抗癌功效的依据之一。

　

 

图示：转移性乳腺癌细胞(绿色)位于大脑血管(红色)上，被星形神经细胞(青色)包围。

Fred Hutchinson癌症研究中心的研究人员正试图了解允许转移细胞播下并生长新的肿瘤的分子信号，以及如何阻止扩散。图中，转移性乳腺癌细胞(绿色)位于大脑血管(红色)上，被星形细胞(青色)包围。

希瑟·赫德博士/加加实验室/弗雷德·哈奇拍摄

 

在某些方面，癌症是令人发狂的统一。肿瘤中不同的细胞并不是完全相同的，但总的来说，它们是由相同的，统一的目标驱动的:生长和分裂，生长和分裂，生长和分裂。但是有一天，在足够的生长和分裂之后，这些细胞中的一小部分会改变这种趋势，做一些不同的事情-

他们转移。

 

转移，或癌症扩散，是复杂的，很大程度上仍然是神秘的。这些特立独行的细胞必须经历无数的改变，因为他们从最初的原发肿瘤到在全身播下种子并形成的新肿瘤。

 

他们从静止状态转变为移动状态，积极地推动自己走出肿瘤之家。它们破坏血管壁或淋巴结。它们在奇怪的新环境和循环系统的物理力量中生存下来。在他们的最终目的地，他们又反过来做了所有这些步骤，重新建立商店，并触发转移瘤的生长。

 

转移是非常低效的。一些大的肿瘤可能每天会有超过一百万的细胞流入血液，但是这些细胞中只有少数会形成新的转移性肿瘤。如果不是如此致命的话，那几个细胞的成就几乎令人敬畏——根据美国癌症协会(American Cancer Society)的数据，几乎所有死于实体肿瘤的人都是死于转移性疾病。

 

Fred Hutchinson癌症研究中心的博士后研究员、研究黑素瘤转移生物学的Minna Roh-Johnson博士说，尽管如此，仍有很多研究人员不了解这个过程，更不用说如何阻止它了。

 

她说:“我从自己的 研究和其他人的研究中了解到的关于转移的知识越多，我就越觉得自己的问题越突出。”“几乎每一步都是未知的。”

 

 

乔纳森·库珀博士

弗雷德·哈奇的基础研究员乔纳森·库珀博士研究细胞运动——转移细胞的一个关键特征。

　

　

第一步:第一步

在转移的第一阶段，肿瘤细胞从静止向移动过渡，“走”出原发肿瘤，穿过肿瘤艰苦的环境。弗雷德·哈奇(Fred Hutch)是一位基础科学家，乔纳森·库珀(Jonathan Cooper)博士。他研究的是驱动细胞运动的分子。尽管胚胎发育涉及到“细胞的大量运动”，库珀说，我们出生后的大部分细胞都停留在原地，只有少数例外。

 

你可以把癌细胞想象成小小的本杰明巴顿——它们会回复到成年后的年轻阶段。癌症合作选择了典型的幼年或胎儿基因在生物学的许多方面，包括迁移，快速增长和他们如何专门化或“分化”。“在某种程度上，就像细胞在分化状态方面回到了早期发育阶段一样，它们在移动能力方面也回到了早期阶段，”库珀说。

 

库珀和他的研究小组研究了乳腺细胞在实验室中是如何移动的，它们在培养皿的塑料表面上移动。他的实验室对细胞的内在特性很感兴趣，这些特性促使细胞移动或静止不动。他们正在观察与癌症生长有关的某些基因，或致癌基因，并询问这些基因的活动是否会加速或减慢细胞在实验室培养皿中的传播。

 

但是除了癌细胞本身，转移还有更多的东西。它的邻居也很重要。

Roh-Johnson还研究了癌细胞从静止到运动的转变，但她对癌症周围的“肿瘤微环境”很感兴趣。在Fred Hutch的发展生物学家Cecilia Moens博士的实验室团队中，Roh-Johnson建立了一个系统来实时研究斑马鱼身上的黑色素瘤，观察健康细胞和肿瘤细胞在转移开始时是如何相互作用的。

 

Fred Hutch博士后研究员Minna Roh-Johnson博士研究黑素瘤转移的早期步骤。

 

　

 

她说:“只有在自己的熟识环境中，你才能理解这些复杂的互动。”

Roh-Johnson说，事实上，某些被称为肿瘤相关巨噬细胞的免疫细胞促进了许多转移步骤，包括最早的转移步骤。她希望找到参与这种相互作用的基因，目标是找到新的治疗途径来阻断巨噬细胞的促肿瘤功能，同时不损害其有益功能。

 

第二步: 穿越障碍，急流中幸存

一旦转移细胞移动，它们就会冲出肿瘤，穿过其他坚硬的细胞和分子层，直到到达血管或淋巴系统。在这里，癌症也劫持了健康的细胞来帮助完成其肮脏的工作。与肿瘤相关的巨噬细胞与其他正常细胞一样，也会参与进来。其中一些细胞分泌特殊的蛋白质，帮助溶解肿瘤坚硬的外膜，以及肿瘤和健康器官周围的细胞外基质分子的黏性、纤维性集合，使癌细胞易于通过血管。

 

一旦肿瘤细胞满足血管的界限,他们可以摆动通过细胞之间的紧密连接,构成血管壁或—而这正是它开始很奇怪——旅行肿瘤细胞可以直接穿过血管细胞,在不伤害这些细胞。

 

“它们把细胞变成了甜甜圈，”库珀说。“它们并没有破坏细胞膜，它们把两个细胞表面推到一起，它们就像熔合一样，所以你最后得到一个甜甜圈，它们穿过中间。”

 

一旦肿瘤细胞进入血管，它们就在时间轴上，Fred Hutch乳腺癌转移研究人员Cyrus Ghajar说。

 

“他们基本上需要三天左右的时间才能退出血循环。如果他们不离开血液，他们就会死。“癌细胞并不是用来做这些事情的……在血液中存活，并在很长一段时间内应对血液的剪切压力。”

　

　

Figure: Representative image of a circulating tumor cell cluster isolated from the blood of a patient with breast cancer and stained with wide-spectrum cytokeratin (red) and DAPI (nuclei, blue).

图:从乳腺癌患者血液中分离出来的循环肿瘤细胞簇（CTC-cluster) 的代表性图像，用广谱细胞角蛋白(红色)和DAPI(蓝色细胞核)染色。

　

 

一些细胞——比如免疫细胞——是为了抵抗循环系统的物理力量而构建的。但是对于一个在静止环境中出生的细胞来说，比如肿瘤细胞，血液每小时3到4英里的流速让人头晕目眩。Kevin张博士也是哈奇癌症转移研究人员，他最近的一项研究发现，乳腺癌转移细胞聚集在一起，成群结队地 转移，就像“一群暴徒”。张和他的同事发现，从他们在体内的旅程开始到结束，粘在一起的细胞似乎比分开的细胞存活得更好。而这些团簇实际上可以使自己变得更薄，从而挤过紧密的毛细血管。(有关张的更多研究，请参阅周三的《哈奇新闻》(Hutch News):“我觉得今年就是这样。”)

所以他们必须想办法出去。

　

塞勒斯盖杰尔博士

乳腺癌转移研究员Cyrus Ghajar博士研究转移性肿瘤细胞如何在体内保持休眠状态，以及如何唤醒它们。

 

 

第三步:找一个新家

Ghajar的研究表明，血管的外边缘似乎是肿瘤细胞流动的一种特殊绿洲。如果它们能在三天之内从血液中逃出来，并留在血管壁上，它们就会受到保护。这些循环的河岸保护肿瘤细胞免受免疫系统的破坏，但它们也在一定程度上保护了病人。

 

在这些特殊的庇护所中，肿瘤细胞保持着“休眠”状态，或处于休眠状态，不分裂。Ghajar和他的研究小组已经在一些转移区域(肺和骨髓)中发现了有助于这种休眠的分子，他们希望能够操纵这种自然系统，以防止转移细胞醒来。

　

 

至于细胞在哪里定居，很明显，转移性肿瘤倾向于身体的某些部位，如骨骼、肝脏、肺或大脑，但原因尚不完全清楚。在某些情况下，癌细胞似乎不分青红皂白地扩散到全身，但大多数器官的条件不利于新的肿瘤生长，因此它们要么处于休眠状态，要么死亡。

 

加贾尔说:“这就像如果我把100颗种子从这栋建筑的屋顶上扔下去，我们不会在美景镇周围种出100株植物。”“它们必须在土壤上着陆，土壤必须有利于它们生长。”

 

 

但是从康奈尔大学的科学家最近的研究和其他人(包括盖杰尔)发现,肿瘤也可以 在转移细胞到达特定器官之前,向其发出信号分子使它们、建立一个对转移肿瘤细胞更有利 的微环境。

 

“所有这些发生在肿瘤细胞出现之前，”Ghajar说。“在这个器官的微小进化过程中，已经为肿瘤细胞建立了一个非常有利的微环境。当这种情况发生时，他们是更有效的转移者。

　

 

第四步:醒来

目前尚不清楚为什么一些转移性细胞在扩散后保持休眠状态这么长时间，而另一些细胞在扩散后相对较快地苏醒。Ghajar说，大约五分之一的转移性乳腺癌患者在接受治疗10年后才会发生转移。

 

他说:“你可以想象这是多么令人沮丧。”“这是毁灭性的，但在治疗10年后，你认为自己已经痊愈，突然又复发了。”

 

在加州大学伯克利分校(University of California, Berkeley)的乳腺癌研究人员米娜·比斯尔(Mina Bissell)博士的博士后研究期间，Ghajar发现，当血管结构发生改变时，那些处于休眠状态的转移细胞会摆脱休眠状态，开始分裂。

 

一旦这些细胞苏醒，它们往往比原来的肿瘤对化疗更有抵抗力——这也是转移如此致命的原因之一。Ghajar的研究团队正在研究这些细胞在休眠期间会做什么，是什么让它们苏醒，以及为什么在传统的治疗方法下，它们一醒来就会变得如此强壮。

 

 

在这里，邻里关系也很重要。

Ghajar和他的团队已经发现，血管周围的区域，除了保持细胞睡眠，也提供治疗抵抗。他们想要确定所涉及的特定分子，并最终以一种新的转移方式阻断这些分子——乳腺癌患者在最初的治疗过程中可以接受的一种预防化疗。

 

“为什么不找到一种方法，让化疗变得更有效，让一些人已经变得更有效率呢?”我们想要防止他们在五到十年后回头看，怀疑癌症是否会复发。

　

 

后记:转移能在开始前停止吗?

转移有一个肮脏的小秘密。

有时，转移细胞在病人的原发肿瘤被诊断之前就已经在全身播撒。多达5%的转移性癌症患者有一种未知的原发疾病，这意味着他们的医生无法确定癌症的起源地——原发肿瘤在扩散前没有被发现。

 

这一现象说明了筛查和早期发现的重要性，但即使原发肿瘤尚未被发现，转移也可以开始。研究人员发现，从这些微小肿瘤脱落的细胞更容易扩散和播撒新的转移性肿瘤。

 

Ghajar认为，预防或治疗转移的新疗法需要关注那些早期传播者的生物学。当一个原发肿瘤被发现时，从遗传学角度看，它可能与肿瘤早期释放的转移细胞非常不同，而现在，转移细胞可能潜伏在患者全身。

 

对Ghajar和他的同事们来说，在新的治疗途径上的工作，这种(甚至更令人沮丧的)转移意味着他们可能有最好的机会帮助大多数转移性癌症患者，方法是集中精力阻止转移过程的后期步骤。

 

他说:“我们不是要阻止 扩散，而是要阻止转移。”“转移到另一个器官是转移的主要步骤，但定居是关键的一步。”如果我们能预防这种情况，那么我们仍能阻止(转移性)癌症的死亡。

加入谈话。在我们的Facebook页面上谈论这个故事。

 

Rachel Tompa是Fred Hutchinson癌症研究中心的前特约撰稿人。她拥有加州大学旧金山分校的分子生物学博士学位和加州大学圣克鲁斯分校的科学写作证书。在Twitter上关注她@Rachel_Tompa。

 

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标签:基础科学，乳腺癌，癌症转移，Cecilia B Moens, Cyrus Ghajar，发育生物学，Jonathan A Cooper, Kevin张，黑色素瘤，转移，乳腺癌转移，转移微环境，公共卫生科学，斑马鱼

 

The science of cancer spread

 

The how and why of metastasis — and what it might take to stop it

April 28, 2016

 |  By Rachel Tompa / Fred Hutch News Service

Metastatic breast cancer cells (green) sit on blood vessels (red) in the brain, surrounded by star-shaped nervous cells known as astrocytes (cyan).

Researchers at Fred Hutch are trying to understand the molecular signals that allow metastatic cells to seed and grow new tumors — and how to stop that spread. Here, metastatic breast cancer cells (green) sit on blood vessels (red) in the brain, surrounded by star-shaped brain cells known as astrocytes (cyan).

Photo by Dr. Heather Herd / Ghajar Lab / Fred Hutch

Editor’s note: This is the second in a two-part series on metastasis. Read part one, about patients living with metastatic breast cancer, here.

 

In some ways, cancer is maddeningly uniform. Different cells in a tumor aren’t all identical, but in a general sense, they are driven by the same, unifying goal: grow and divide, grow and divide, grow and divide. But one day, after enough growing and dividing, a tiny minority of those cells bucks the trend and does something different.

 

They metastasize.

 

Metastasis, or cancer spread, is complex and still largely mysterious. Those maverick cells have to go through myriad changes as they traverse the path from their original home in the primary tumor to new tumors they seed and form throughout the body.

 

They change from stationary to mobile, actively pushing their way out of their tumor home. They breach the walls of blood vessels or lymph nodes. They survive the strange new environment and physical forces of the circulatory system. And at their final destination, they do all these steps again in reverse, setting up shop anew and triggering the growth of a metastatic tumor.

 

Metastasis is very inefficient. Some large tumors may shed upward of a million cells into the bloodstream every day, but only a few of these cells actually form new metastatic tumors. If it weren’t so deadly the feat of those few cells would be almost awe-inspiring — nearly all deaths from solid tumor cancers are due to metastatic disease, according to the American Cancer Society.

 

Even so, there’s still a ton researchers don’t understand about the process, let alone how to stop it, said Fred Hutchinson Cancer Research Center postdoctoral fellow Dr. Minna Roh-Johnson, who studies the biology of melanoma metastasis.

 

“The more I learn about metastasis from my work and other people’s work, the more outstanding questions I feel like get added to the list of outstanding questions,” she said. “Almost every step is an unknown.”

 

Dr. Jonathan Cooper

Fred Hutch basic researcher Dr. Jonathan Cooper studies cell movement — a key characteristic of metastatic cells.

Fred Hutch file

Step one: First steps

 

In the first stage of metastasis, tumor cells make the transition from immobile to mobile, “walking” their way out of the primary tumor and through the tumor’s tough surroundings. Changing from static to mobile is yet another way that cancer cells are different from typical adult cells, said Fred Hutch basic scientist Dr. Jonathan Cooper, who studies the molecules that drive cell movement. While embryonic development involves “mass movements of cells,” Cooper said, most of our cells after we’re born stay where they are, with a few minor exceptions.

 

You could think of cancer cells like tiny Benjamin Buttons — they revert back to younger versions of their adult selves. Cancer co-opts typically juvenile or fetal genes for many aspects of its biology, including migration, rapid growth and how specialized — or “differentiated” — they are.“In a way, just as the cells go back to an earlier developmental stage in terms of their differentiation state, so they go back to an earlier stage in terms of their ability to move,” Cooper said.

 

Cooper and his research team study how breast cells migrate in the lab, pushing their way across the plastic surfaces of petri dishes. His lab is interested in the intrinsic properties of cells that trigger them to move — or to stay still. They’re looking at certain genes involved in cancer growth, or oncogenes, and asking whether changing the activity of those genes speeds or slows the cells’ path across the lab dishes.

 

But there’s more to metastasis than the cancerous cell itself. Its neighbors matter too.

 

Roh-Johnson also studies cancerous cells’ shift from immobility to movement, but she’s interested in cancer’s surroundings, the “tumor microenvironment.” Working in the laboratory team of Fred Hutch development biologist Dr. Cecilia Moens, Roh-Johnson has established a system to study melanoma in real-time in the see-through zebrafish — to see how healthy cells and tumor cells interact as metastasis begins.

 

Dr. Minna Roh-Johnson

Fred Hutch postdoctoral research fellow Dr. Minna Roh-Johnson studies the early steps in melanoma metastasis.

Photo by Robert Hood / Fred Hutch News Service

“It’s really only when you’re in your native environment that you can understand these complex interactions,” she said.

 

In turns out that certain immune cells known as tumor-associated macrophages promote many steps of metastasis, including the earliest ones, Roh-Johnson said. She’s hoping to find the genes involved in this interaction — with the goal of finding new treatment avenues to block macrophages’ pro-tumor functions while leaving their helpful functions unharmed.

 

Step two: Breaking barriers and surviving torrents

 

Once the metastatic cells gain mobility, they push their way out of their native tumor and through other layers of tough cells and molecules until they reach a blood vessel or the lymph system. Here, too, cancer hijacks healthy cells to help do its dirty work. Tumor-associated macrophages come along for the ride, as do other normal cells. Some of these cells secrete special proteins that help dissolve the tumor’s tough outer membrane and the sticky, fibrous collection of molecules known as the extracellular matrix surrounding both tumors and healthy organs, allowing the cancer cells easy passage on their march toward blood vessels.

 

Once the tumor cells meet the boundaries of blood vessels, they can wiggle their way through the tight junctions between the cells that make up those vessel walls or — and here’s where it starts getting really weird — traveling tumor cells can actually pass directly through the middle of blood vessel cells, without harming those cells.

 

“They turn the cell essentially into a donut,” Cooper said. “They’re not breaking the cell’s membrane, they push the two cell surfaces together and they kind of fuse, so you end up with a donut and they go through the middle.”

 

Once the tumor cells are inside blood vessels, they’re on a timeline, said Fred Hutch breast cancer metastasis researcher Dr. Cyrus Ghajar.

 

“They basically need three days or so to get out of circulation. If they don’t get out of circulation then they’re going to die,” he said. “A carcinoma cell wasn’t ever built to do that … surviving in the blood and dealing with the shear stress of the blood for an extended period of time.”

 

Some cells — like immune cells — are built to withstand the circulatory system’s physical forces. But for a cell born in a stationary environment, like a tumor cell, the blood’s dizzying 3 to 4 mph speed is stressful. Recent research from Dr. Kevin Cheung, also a breast cancer metastasis researcher at the Hutch, has found that breast cancer metastatic cells stick together and travel in clumps, like “a gang of thugs.” From the beginning to the end of their journey through the body, cells that stick together seem to survive better than apart, Cheung and his colleagues found. And the clusters can actually make themselves thinner to squeeze through tight capillaries. (For more on Cheung’s research, see Wednesday’s Hutch News story “I feel like this is the year.”) But together or alone, the tumor cells can’t survive indefinitely in the bloodstream.

 

So they have to look for a way to get out.

 

Dr. Cyrus Ghajar

Breast cancer metastasis researcher Dr. Cyrus Ghajar studies how metastatic tumor cells remain dormant in the body — and what wakes them up.

Photo by Bo Jungmayer / Fred Hutch News Service

Step three: Finding a new home

 

Ghajar’s research has shown that the outer edge of the blood vessel seems to be a special kind of oasis for traveling tumor cells. If they can make it out of the blood in less than three days and remain right next to the vessel wall, they’re protected. These circulatory river banks protect the tumor cells from destruction by the immune system, but they also protect the patient — to a point.

 

The tumor cells stay “dormant,” or asleep and undividing, in those special sanctuaries. Ghajar and his research team have identified molecules in some metastatic areas (the lung and bone marrow) that contribute to that dormancy, with the ultimate hope of manipulating that natural system to keep metastatic cells from ever waking up.

 

As for where the cells settle, it’s clear that metastatic tumors trend toward certain parts of the body – such as the bones, liver, lungs or brain — but it’s not completely clear why. In some cases, cancer cells seem to spread indiscriminately throughout the body, but conditions aren’t favorable for new tumor growth in most organs, so they remain dormant or die.

 

“It’s like if I threw 100 seeds off the roof of this building, we wouldn’t end up with 100 plants sprouting around Fairview,” Ghajar said. “They’d have to land on soil and that soil would have to be favorable for them to grow.”

 

But recent research from scientists at Cornell University and others (including Ghajar) has found that tumors can also prime certain areas of the body for metastasis before the cells ever reach it, sending out molecular packages that home specifically to other organs and render them a more fertile ground for metastatic cells.

 

“All of this happens before a tumor cell even shows up there,” Ghajar said. “Over the course of this little evolution of the organ, a very favorable microenvironment has been set up for tumor cells. … They’re far more effective metastasizers when this happens.”

 

Step four: Waking up

 

It’s not clear why some metastatic cells stay dormant for so long while others wake up relatively soon after spreading. About one in five metastatic breast cancer patients won’t get metastases until 10 years after they’ve been treated, Ghajar said.

 

“You can imagine how crushing that is,” he said. “It’s crushing across the board, but you go 10 years after treatment, you think you’re cured, and all of a sudden you have a relapse.”

 

During his postdoctoral fellowship with breast cancer researcher Dr. Mina Bissell of the University of California, Berkeley, Ghajar found that when blood vessels change their structure, the metastatic cells sitting in dormancy near those vessels shake off their stupor and start to divide.

 

And once those cells wake up, they are often much more resistant to chemotherapy than the original tumor — one of the reasons metastasis is so deadly. Ghajar’s research team is studying what the cells do during dormancy, what wakes them up and why they’re so much stronger in the face of conventional treatments once they reawaken.

 

Here, too, the neighborhood matters.

 

Ghajar and his team have found that the area right around the blood vessels, besides keeping cells asleep, also confers therapeutic resistance. They want to pinpoint the specific molecules involved and eventually interrupt those molecules with a new kind of metastasis-preventing chemo that breast cancer patients could receive during their initial treatment.

 

“Why not find a way to make chemotherapy that someone’s already going to get far more effective? We want to prevent them from looking over their shoulder in five or 10 years, wondering if the cancer’s going to come back,” Ghajar said.

 

Postscript: Can metastasis be stopped before it starts?

 

Metastasis has a dirty little secret.

 

Sometimes, metastatic cells are seeded throughout the body before a patient’s primary tumor is even diagnosed. Up to 5 percent of patients with metastatic cancer have what’s known as an unknown primary, meaning their doctors can’t figure out where the cancer started — the primary tumor wasn’t detected before it started spreading.

 

This phenomenon points to the importance of screening and early detection, but metastasis can begin even when the primary tumor is not yet detectable. Researchers have seen that the cells shed from these tiny tumors are better at spreading and seeding new metastatic tumors.

 

Ghajar believes that new therapies to prevent or treat metastasis need to focus on the biology of those early spreaders. By the time a primary tumor is detected, it may look very different, genetically speaking, from any metastatic cells released from that tumor earlier in its lifetime — and which now may be lying dormant throughout the patient’s body.

 

For Ghajar and his colleagues working on new therapeutic avenues, this (even more) depressing side of metastasis means that they may have the best chance of helping the most people with metastatic cancer by focusing on stopping the later steps of the process.

 

“We’re not trying to stop dissemination, but we are trying to stop metastasis,” he said. “Getting to another organ is most of metastasis, but colonization is the key step. If we can prevent that, then we’re still stopping [metastatic] cancer dead in its tracks.”

 

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Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.

 

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TAGS: Basic Sciences, Breast Cancer, cancer metastasis, Cecilia B Moens, Cyrus Ghajar, developmental biology, Jonathan A Cooper, Kevin Cheung, Melanoma, metastasis, metastatic breast cancer, metastatic microenvironments, Public Health Sciences, zebrafish