This fluorescent image shows endothelial cells embedded in a scaffold made of collagen. The cell nuclei are blue, and actin inside the cells shows up as red. Image: Joseph Franses |
MIT scientists have discovered that
cells lining the blood vessels secrete molecules that suppress tumor growth and
keep cancer cells from invading other tissues, a finding that could lead to a
new way to treat cancer.
Elazer Edelman, professor in the
MIT-Harvard Division of Health Sciences and Technology (HST), says that
implanting such cells adjacent to a patient’s tumor could shrink a tumor or
prevent it from growing back or spreading further after surgery or
chemotherapy. He has already tested such an implant in mice, and MIT has
licensed the technology to Pervasis Therapeutics, Inc., which plans to test it
in humans.
Edelman describes the work, which
appears in Science Translational Medicine,
as a “paradigm shift” that could fundamentally change how cancer is understood
and treated. “This is a cancer therapy that could be used alone or with
chemotherapy radiation or surgery, but without adding any devastating side
effects,” he says.
Cells with many functions
Cells that line the blood vessels, known as endothelial cells, were once
thought to serve primarily as structural gates, regulating delivery of blood to
and from tissues. However, they are now known to be much more active. In the
1980s, scientists discovered that endothelial cells control the constriction
and dilation of blood vessels, and in the early 1990s, Edelman and his
postdoctoral advisor, Morris Karnovsky, and others, discovered an even more
important role for endothelial cells: They regulate blood clotting, tissue
repair, inflammation, and scarring, by releasing molecules such as cytokines
and large sugar-protein complexes.
Many vascular diseases, notably atherosclerosis,
originate with endothelial cells. For example, when a blood vessel is injured
by cholesterol, inappropriately high blood sugar, or even physical stimuli,
endothelial cells may overreact and provoke uncontrolled inflammation, which
can further damage the surrounding tissue.
Edelman and HST graduate student Joseph
Franses hypothesized that endothelial cells might also play a role in
controlling cancer behavior, because blood vessels are so closely entwined with
tumors. It was already known that other types of cells within tumors, known
collectively as the tumor stromal microenvironment, influence cancer cell
growth and metastasis, but little was known about how endothelial cells might
be similarly involved.
In the new study, Edelman, Franses and former
MIT postdoctoral fellows Aaron Baker and Vipul Chitalia showed that secretions
from endothelial cells inhibit the growth and invasiveness of tumor cells, both
in cells grown in the lab and in mice. Endothelial cells secrete hundreds of
biochemicals, many of which may be involved in this process, but the
researchers identified two that are particularly important: a large
sugar-protein complex called perlecan, and a cytokine called interleukin-6.
When endothelial cells secrete large amounts of perlecan but little IL-6 they
are effective at suppressing cancer cell invasion, whereas they are ineffective
in the opposite proportions.
The researchers theorize that there is a
constant struggle between cancer cells and endothelial cells, and most of the
time, the endothelial cells triumph. “All of us, every day, are exposed to
factors that cause cancer, but relatively few of us exhibit disease,” says
Edelman. “We believe that the body’s control mechanism wins out the bulk of the
time, but when the balance of power is reversed cancer dominates.”
The struggle also depends on a third
player, the endothelial cells’ extracellular matrix. Endothelial cells only
function properly when their extracellular matrix is stable and of the correct
biochemical composition. Under normal conditions, if a cell becomes cancerous,
the endothelial cell may then keep it in check. However, the cancer cell fights
back by trying to destroy the extracellular matrix or change the endothelial
cell directly, both of which hinder the endothelial cell’s efforts to control
the cancer.
“There is this three-way balance that
needs to be achieved,” says Edelman. The more aggressive a cancer cell, the
more likely it is to overcome the endothelial cells and extracellular matrix,
allowing it to spread to other tissues.
Jack Lawler, professor of pathology at Harvard Medical School,
says the new work “opens the door to many avenues” of future research. “The
history of cancer research has really focused on tumor suppressor genes and
oncogenes as the sole effectors of cancer.” While attention has turned to other
cell types in the past 15 years, “the endothelial cell, for the most part, has
not been considered in that context,” says Lawler, who was not part of the
research team.
Cells on a scaffold
Several years ago, Edelman began using endothelial cells, grown within a
scaffold made of denatured, compressed collagen, as an implantable device. The
“matrix-embedded endothelial cells” served as a convenient unit that could be
produced in bulk, tested for quality control, retained intact for months and
implanted immediately when needed. This way, the healthiest cells could be
selected to secrete all of the chemicals normally released by endothelial cells
and placed in multiple locations in the body to control disease.
In clinical trials these implants were
placed around blood vessels after vascular surgery and controlled local
clotting and infection better than devices without cells. Significantly,
because the endothelial cells were associated with a matrix mimicking their
natural state, even cells from other people could be implanted without being
rejected by the patients’ immune systems. No major side effects were seen in
the clinical trials.
“Blood vessels and endothelial cells are
the perfect regulatory units and our synthetic device recapitulated these
control units perfectly,” says Franses. Blood vessels penetrate to the deepest
recesses of tumors, and in doing so carry the powerful regulatory endothelial
cells as close to cancer cells as possible. The extracellular matrix backbone
of the vessels can keep the endothelial cells healthy and the healthy endothelial
cells control nearby cancer cells. “This is what we mimicked with our devices,”
he says. “In a sense it is like putting a cellular policeman on the corner of
every tumor neighborhood.”
In one mouse experiment reported in the
new paper, endothelial cell implants significantly slowed tumor growth and
prevented gross destructive change in tumor structure. Another experiment
showed that cancer cells that had been grown in the secretions of endothelial
cells were less able than standard cancer cells to metastasize and colonize the
lungs of mice.
The new findings could also explain why
drugs that suppress angiogenesis have shown only transient and moderate benefit
for cancer patients thus far. “You starve the tumor of its blood supply, but
you also damage tumor blood vessel endothelial cells, so when the tumor comes
back, there’s nothing to keep it in check. The vessels feed the tumor but their
endothelial cells control the cancer cells within. Giving the endothelial cells
without the blood vessels provides the best of both worlds and perhaps one day
could provide new means of cancer therapy,” says Edelman.
