In The Bloodstream
A team of scientists at The Scripps Research Institute has identified a potential treatment strategy against metastatic cancer
cells that has never been tried before.
Metastasis is a major problem with cancer because it allows tumor cells to spread to other parts
of the body (See Supporting Material: Cancer and Metastasis). While solid tumors can be removed surgically or treated with
chemotherapy or radiation, metastatic cells that have already entered the circulation are capable of opening a passageway
through blood vessels in order to spread to various organs throughout the body.
Once tumor cells leave their primary tumor, they enter the blood stream and ultimately must find
an exit strategy in order to set up new "satellite" lesions in one or more distant organs. The potential treatment strategy
targets this final step of the metastatic cascade--the exit of the metastatic cells from the bloodstream.
"We know that the normal blood vessel wall is one final barrier that metastatic tumor cells must
overcome, which allows them to find their way out of the bloodstream and into a metastatic site," says Immunology Professor
David A. Cheresh, who led the research with postdoctoral fellow Sara Weis at The Scripps Research Institute. To exit the blood
stream, says Cheresh, the tumor cells stimulate the local blood vessels to briefly open their cell-cell junctions so that
they can implant themselves into a new organ site.
In the latest issue of the Journal of Cell Biology, Cheresh, Weis, and their colleagues report
the dramatic effect of using a class of compounds known as Src kinase inhibitors to treat metastatic cancer in mice. Rather
than conventional chemotherapies, which target the tumor cells, Cheresh and colleagues suggest a new approach that would increase
the protective barrier strength of the host blood vessels and prevent tumor cells from exiting the bloodstream.
To support their approach, Cheresh, Weis, and their colleagues demonstrate that mice that are genetically
deficient in the Src gene are resistant to tumor cell metastasis. Furthermore, blocking Src in normal mice dramatically protects
the mice against metastatic tumors because it keeps the cancer cells "sandbagged" in the bloodstream where they are vulnerable
to attack and clearance from the immune system.
"You can imagine that a prolonged treatment [with Src kinase inhibitors] may actually help people
ward off some of the most deadly and metastatic cancers," says Cheresh. "Currently, anti-cancer drugs are typically aimed
at the tumor cells themselves. The problem is that genetically unstable tumor cells are able to develop resistance to one
or more drugs, ultimately overwhelming the host. We keep changing the combination, and the cells keep picking the lock. With
this new approach, we are essentially bolting the door closed."
Sandbagging Cancer Cells
The possible new treatment strategy for cancer cell metastasis stems from several years of basic
research conducted by Cheresh and his collaborators into an area of biology known as cell adhesion.
Cell adhesion is a topic of major importance because it is the basis for how groups of cells form
and define functionally distinct tissues and organs in the body. Blood vessels are lined by what are known as endothelial
cells, which adhere to one another and line the body's blood vessels like bricks lining a subterranean tunnel.
Cheresh and other basic science researchers over the past decades have identified a number of the
adhesion molecules that hold these endothelial cells together. They have also identified the signaling mechanisms that defeat
cell adhesion and induce endothelial cells to let go of one another during events like angiogenesis--the growth of new blood
vessels that often accompanies tumor growth.
Some of the most metastatic tumor cells secrete a protein known as vascular endothelial growth
factor (VEGF). VEGF stimulates a protein called Src kinase, which causes proteins known as cadherins to disengage from each
other. Normally, cadherins are something like the mortar in between the endothelial cell bricks, and they maintain the integrity
of blood vessel walls. When tumor cells release VEGF within blood vessels, Src kinases respond to this by causing the vascular
cell cadherins to break apart and allow the tumor cell to get out of the circulation and into an environment where the tumor
cell can survive and propagate.
Blocking the Exits
Targeting growth factors like VEGF or its downstream target Src is an emerging paradigm for fighting
cancer. In fact, the U.S. Food and Drug Administration recently approved Avastin, a VEGF inhibitor, for fighting colorectal
However, VEGF is unique among growth factors in that it also causes vascular permeability where
it is released. This is easily seen when looking at the blood supply to tumors under the microscope, says Cheresh. "Anywhere
there is VEGF, there is a vascular permeability," he says. "Tumors have blood vessels that are very leaky."
Once in the circulation, tumor cells can travel to distant parts of the body. Often tumor cells
that are in the bloodstream get lodged in small blood vessels. Up until now it has not been clear how the tumor cells actually
get out of these vessels and form new tumors in distant organs, says Cheresh, but part of the answer may lie in the fact that
these cells release VEGF when they are in the bloodstream, and the VEGF allows them to enter into the tissue.
Cheresh, Weis, and their colleagues thought that if they could prevent this by blocking VEGF or
Src kinase--in essence, sandbagging the tumor cells in the bloodstream--this might have a positive therapeutic effect on patients
with metastatic cancer, because the human immune system handles tumor cells very well if they are in the circulation.
"Tumor cells don't last in the circulation," explains Cheresh. "If you can increase the dwell time
that tumor cells spend in circulation by reducing their capacity to get out, you effectively give the immune system a greater
chance of winning the battle."
Cheresh, Weis, and their colleagues decided to test whether blocking VEGF-induced vascular permeability
with something known as a Src kinase inhibitor might turn off metastatic tumor cells' exit strategy from the bloodstream.
They examined the question by turning to a special type of mouse that Cheresh and his colleagues have used in their laboratory.
These mice, born without the ability to make Src kinase protein, show no vascular leak response.
In laboratory studies, these animals showed a high degree of resistance to tumor metastasis. Separate
experiments showed that normal mice treated with Src kinase inhibitors also acquired a high degree of resistance to the metastasis
of tumor cells.
This suggests a possible new avenue to explore therapeutically in humans. Src kinase inhibitors
might reduce the metastatic ability of cancer cells and improve the prognosis of patients treated with them.
Significantly, this approach reduces cancer cell metastasis by targeting a host protein (Src kinase),
which means that it may be broadly applicable in many different types of cancer. Indeed, Cheresh and Weis tested Src kinase
inhibitors against several types of metastatic cancer cell lines and found that it did work against most of them.
Of course, such a treatment strategy would have to be explored in the context of clinical trials
before doctors knew for sure if it would work in humans, and these may take several years.
Source: Scripps Research Institute