In the Lab

On Cancer: Holding On and Hiding Out: How Cancer Cells Spread to the Brain and Thrive

By Eva Kiesler, PhD, Science Writer/Editor  |  Thursday, February 27, 2014
 Pictured: Cancer cell on blood vessel This image shows a breast cancer cell (green) clinging to a blood capillary (purple) in the brain.

Metastasis, the process that allows some cancer cells to break off from their tumor of origin and take root in a different tissue, is the most common reason people die from cancer. Yet most tumor cells die before they reach their next destination, especially if that destination is the brain. In people with lung cancer, for example, occasional tumor cells may enter the bloodstream and infiltrate the brain, but very few survive long enough to seed new tumors.

Now a team of Memorial Sloan Kettering scientists has looked into why most circulating tumor cells die upon reaching the brain and why, in exceptional cases, other cells don’t. Their latest study, published today in the journal Cell, identifies genes and proteins that control the survival of metastatic breast and lung cancer cells in the brain.

These survival factors might one day be targeted with drugs to further diminish people’s risk of metastasis. According to the study’s senior author, Sloan Kettering Institute Director Joan Massagué, a single mechanism is likely to enable cancer cells to colonize various organs, including the brain, in a number of disease types.

An Understudied Disease Type

Metastatic brain tumors occur in several types of cancer — including breast, lung, and colorectal cancer, among others — and are estimated to be about ten times more common than primary brain cancers. Until now, little research has been done into how metastatic brain tumors develop.

Dr. Massagué and his coworkers began to tackle this problem four years ago and have since learned that the brain is better protected than most organs against colonization by circulating tumor cells. To seed in the brain, a cancer cell must dislodge from its tumor of origin, enter the bloodstream, and cross a densely packed vasculature structure called the blood-brain barrier. Mouse experiments in which metastatic breast cancer cells were labeled and imaged over time revealed that a very small number were able to complete this journey, and of those cells that did make it to the brain, fewer than one in 1,000 survived.

“We didn’t know why so many of these cells die,” Dr. Massagué says. “What kills them? And how do occasional cells survive in this vulnerable state — sometimes hiding out in the brain for years — to eventually spawn new tumors? What keeps these rare cells alive and where do they hide?”

Dodging Death Signals

To answer these questions the researchers conducted experiments in mouse models of breast and lung cancer, two tumor types that often spread to the brain, investigating a panel of genes that have been linked to brain metastasis. Their research revealed that many cancer cells that enter the brain are killed by astrocytes — the most common type of brain cell — that secrete a protein called Fas ligand.

When cancer cells encounter this protein, they are triggered to self-destruct by the activation of an internal death program. The study also showed that the exceptional cancer cells that escape do so by producing a protein called Serpin, which acts as a sort of antidote to the death signals fired at them by nearby astrocytes.

Hugging Blood Vessels

The researchers used imaging methods to examine the behavior of these defiant metastatic cells in the brains of mice. They noticed that the surviving cells grew on top of blood capillaries — each cell sticking closely to its vessel “like a panda bear hugging a tree trunk,” Dr. Massagué says.

“This hugging is clearly essential,” he explains. “If a tumor cell detaches from its vessel, it gets killed by nearby astrocytes. By staying on, it gets nourished and protected, and may eventually start dividing to form a sheath around the vessel.”

Under the microscope, the researchers watched these sheaths grow into tiny balls, which eventually became tumors. “Once you’ve seen it, you can never forget this image,” Dr. Massagué says.

The scientists also did experiments to pinpoint the molecular basis of the cells’ behavior and showed that a protein produced by the tumor cells acts as a kind of Velcro, attaching the cells to the outer wall of a blood vessel.

Therapeutic Ideas

The findings give scientists new possibilities to understand and study the biology of metastasis, and could also lead to the development of new therapies that would work by strengthening the natural impediments to metastasis. The study identifies several mechanisms such drugs could target. Dr. Massagué is particularly interested in the ability of some tumor cells to hug blood vessels, as he suspects this behavior may be essential for the survival of metastatic cancer cells not only in the brain but also in other parts of the body where metastatic tumor growth can occur.

“Most cancer patients are actually at risk of having their tumor spread to multiple sites,” Dr. Massagué notes. For example, breast cancers can metastasize to the bones, lungs, and liver as well as to the brain. “What we may be looking at,” he adds, “is a future way to prevent metastasis to many organs simultaneously,” using drugs that make tumor cells let go of the blood vessels they cling to. 

This study was supported by the National Institutes of Health under grant numbers P01-CA129243 and U54-163167; a U.S. Department of Defense Innovator award, number W81XWH-12-0074; the Alan and Sandra Gerry Metastasis Research Initiative; and the Hope Funds for Cancer Research.

Comments

I want to learn more. Please keep me posted on the latest articles. They makes a difference. I believe Memorial Sloan Kettering is the best cancer hospital in the city

Dear Horricka, to keep abreast of our news and research advances, you may be interested in subscribing to our e-newsletter. Browse previous issues and subscribe here: http://www.mskcc.org/cancer-care/counseling-support/e-mail-newsletter
Thank you for your comment.

Are there specific cns chemoprophylaxis in lung ca? If so what are they?

Thank you for your comment, Dr. Evboifo. We forwarded your question to medical oncologist Mark G. Kris, one of the researchers involved in the study, and he said no chemoprophylaxis is available for lung cancer at present.

If is it possible for scientists to duplicate more astrocytes and dispatch them to kill cancer cells in breast, lung, intestine or rectum? The spread to brain and hugs on vessels can be terminated and baffled.

What role does VEGF play in metastasis? VEGF is inflammatory. I understand it has a 'sticky' (protein?) component which allows it to adhere to blood vessels, thereby promoting metastasis. There exists a very potent anti-inflammatory protease derived from a specific fungus which is deliverable very successfully into circulation and its (preferred) substrait are pro-inflammatory proteins. If this is true, then the VEGF 'carrier' for cancer cells can be stripped of its ability to adhere to blood vessels thereby exposing the cancer cells to the body's defenses - no metastasis!

Good morning,
A toddler I know is undergoing chemotherapy at your center. Her mother refuses to feed her any kinds of proteins since in her opinion - based on an anecdotal "Dr Laskin diet" - proteins feed cancer, and she is convinced that keeping her child on Dr Laskin diet has kept the tumor from metastasis. She is hiding this fact from a dietitian at your center also (her exact words: "If I tell them my child is on a special diet, they'll tell me to feed meat to her"). The child only eats fresh fruits (especially many apples), berries, some vegetables, and buckwheat soaked in water (raw) - the only times I have seen the child throw tantrums was because of hunger, and the child complained of being hungry every time I asked. The child has been on this diet for over a year I believe and mother does not allow her to eat meat, fish, or nuts. Mother herself is on a meat-free diet. Can you please advise here on whether this diet for the child has any scientific merit and how/whether I should contact your center to notify of this?
Thank you

Jenna, thank you for comment. We are looking into the issue you have raised.

Jenna, to follow up we are unable to discuss specific medical cases or the scientific merit of a particular diet on our blog. But all pediatric patients are under care of experts who are aware of the nutritional needs of the patient and ensure they are met.

To add to my post above, the mother also does not allow the child to consume any dairy products (i.e no milk, cheese, eggs, etc)

This is very intriguing and inspiring research. I am 3 years out from Stage 3A Triple Negative Breast cancer. This research may prove to be valuable in the future. I will most likely always be concerned the breast cancer may have metastized to another part of my body. This research may prove to be helpful in near future. Thank you Sloan Kettering doctors for your ongoing pursuit to learn about how cancer(s) behave.

This is quite interesting and revealing. I hope you talented researchers will be able to develop therapeutic strategies that will counter the serpins and those other proteins that enable tumor cells attach and cling to blood vessels. This will make the treatment of metastatic cancers easy especially in the third world like ours where most of the cases present with metastases.

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