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
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。
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。
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。
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。
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).
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。”)
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。
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。
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。
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.
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