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?”
Back to topDodging 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.
Back to topHugging 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.
Back to topTherapeutic 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.
Back to topComments
Horricka Wilson
Feb 27, 2014 • 6:14 PM
Memorial Sloan Kettering
Feb 27, 2014 • 9:26 PM
In reply to I want to learn more. Please by Horricka Wilson
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.
Dr Nathaniel Evboifo
Feb 28, 2014 • 12:35 AM
Memorial Sloan Kettering
Mar 3, 2014 • 4:04 PM
In reply to Are there specific cns by Dr Nathaniel Evboifo
Thisamy
Feb 28, 2014 • 12:52 PM
Joseph Cerceo
Mar 1, 2014 • 10:35 AM
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!
Jenna
Mar 5, 2014 • 11:23 AM
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
Mar 5, 2014 • 12:00 PM
Elise
Apr 2, 2014 • 5:06 PM
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.
Dr Katung I A
Apr 6, 2014 • 2:30 PM
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.
Pieter
Aug 13, 2014 • 1:42 PM
One very frustrating thing about cancer treatment is that the very same treatment is followed in all the patients although the doctors know it dos not work. Our son had osteosarcoma in stead of advising amputation the doctor advised knee replacement, then when it moved to the lungs the removal of legions. When will doctors admit straight to patients you choose no treatment and save yourself the chemo suffering or all the suffering that come with treatment. It is general accepted knowlage that any sarcoma cancer is fatal. It would however be marvelous if your research can isolate the protien that kills cancer and the substance that prevent the rouge cancer cells to attach to blood vessels.
Pieter, our condolences for your son’s experience with sarcoma. We would like to make clear, however, that sarcoma is often curable and can often be successfully treated without need for amputation or chemotherapy.
You can learn more about the treatment of sarcoma at Memorial Sloan Kettering here:
http://www.mskcc.org/blog/new-information-about-diagnosing-and-treating…
Lillian Hunt
Oct 2, 2014 • 12:14 AM
I have recurring stage4 breast cancer that's spread to my bones, pelvic area (Metastasis.) My husband informed me that my Pastor's wife informed him that a man told her that the reason people have cancer is that they are holding a grudge against someone and need to ask God for forgiveness and to repent. She also told my husband to think about it. My husband didn't want to tell me but he did and thought she was crazy to believe that. What should I do about this. I told my husband I just didn't know who to ask God to forgive because I don't know who to forgive because I don't hold grudges against people. I pray already and I ask God to forgive me for any thing that I have done that's not pleasing in his eye sight. This is crazy to me and my husband. Should I confront her. This is really negative thinking to me.
Lillian,
We are very sorry to hear about your diagnosis. There is actually no evidence that cancer is caused by a person’s emotional state.
If you would like to learn more you can call the National Cancer Institute’s Cancer Information Service at 800-4CANCER (800-422-6237).
Also, at the link below is a video of Memorial Sloan Kettering Craig Thompson discussing how cancer arises in human beings.
http://www.mskcc.org/videos/why-we-all-don-t-get
Thank you for reaching out to us.
Anne Kivari
Dec 7, 2016 • 11:36 PM
Memorial Sloan Kettering
Dec 9, 2016 • 10:34 AM
In reply to I was diagnosed with Stage 2… by Anne Kivari
Dear Anne, we are sorry to hear about your diagnosis. We recommend that you follow up with your oncologist to discuss the specifics around your prognosis. He or she will be most familiar with the details of your health and medical history and is best equipped to answer your questions. Thank you for reaching out to us.
Nan M
Jan 17, 2019 • 4:21 PM
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