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