Tissue Factor in the Fight Against Tumors
By Jason Socrates
Bardi
"The
time has come in America when the same kind of concentrated
effort that split the atom and took man to the moon should
be turned toward conquering this dread disease. Let us make
a total national commitment to achieve this goal."
——Richard
M. Nixon, discussing cancer in his 1971 State of the Union
Address.
When U.S. President Richard Nixon declared war on cancer
in the early 1970s, he was seeking to energize the public
and the scientific community to tackle what was then one of
the leading causes of death in the United States.
Nobody could have known in December 1971, when amidst great
fanfare President Nixon signed the National Cancer Act,
what it would take to win this war. Certainly nobody knew
how long it would take. In fits of irrational exuberance that
are perhaps common at the start of a war, some even predicted
a quick victory—a cure for cancer in five years.
Much has been discovered and reported on cancer in the last
30-odd years —about its causes, prevention, detection,
and treatment—but the battle lines are still drawn. And
in the last three decades we have learned above all that cancer,
like war, is hell.
Cancer is still one of the leading causes of death in the
United States. It is the second leading cause of adult mortality
and the leading cause of child mortality for children under
the age of 15. According to statistics compiled by the National
Institutes of Health, the overall cost of cancer was over
$180 billion in the year 2000 alone, a figure that is dwarfed
perhaps only by the human toll. One new cancer is diagnosed
every 30 seconds in the United States, and every 90 seconds
another American dies of cancer.
A Basic Approach to Killing Tumors
Many of our greatest successes in the struggle against cancer
have come from basic research aimed at understanding the fundamental
molecular and cell biology that produces the condition.
We have learned that cancer is not a single type, but rather
over a hundred different errors in cells of various tissues
caused by various sorts of mutations. Some mutations turn
on or increase the activity of certain key genes, increasing
the expression of metalloproteinases for instance; others
downregulate them, shutting off production of receptor proteins.
Common to tumor cells is their resistance to normal programmed
cell death. Thus they continue to live and proliferate. After
certain mutations occur, a cancer cell grows out of control,
dividing over and over and forming a solid tumor—or,
with leukemias, an every increasing number of circulating
tumor cells in the blood and throughout the body. Tumors often
damage the tissues where they are located and most metastasize
and migrate locally and through the bloodstream—and these
are the tumors that claim so many lives every year.
Whether the wish to arrive at a single cure for cancer will
ever be fulfilled is doubtful. However, the basic science
that has led to a current understanding of the common abnormalities
of many different types of cancer in the last several decades
has yielded a number of new and promising approaches to detection
and treatment.
One novel approach, pioneered by scientists at The Scripps
Research Institute (TSRI) and elsewhere, is to block the flow
of blood to a tumor. For a tumor to grow, it requires access
to growth factors, oxygen, and nutrients supplied through
the bloodstream. Block the blood, the thinking goes, and you
can asphyxiate and/or starve a tumor—like drying out
a lake by diverting all its tributaries. There are a number
of ways to do this— for instance, by inhibiting angiogenesis,
the proliferation of blood vessels supplying a tumor or blocking
the interactions of the required growth factors with tumor
vessels.
TSRI Professor Thomas S. Edgington and members of his laboratory
in the Department of Immunology have been working for several
years on another strategy within this paradigm.
Basically, they are seeking to initiate thrombotic occlusion
of the blood vessels in tumors, effectively blocking the local
flow of blood. This produces a "gangrene" effect in the tumors.
Starved of oxygen, the tumor cells undergo immediate asphyxiation
and tumor cell death on a massive scale.
"You can actually watch the tumors die right in front of
you," says Edgington, who has been refining the technique
for a number of years.
Clearing the Cancer Through Blood Clots
Edgington's technique basically involves delivering molecules
of tissue factor (TF) to tumor vascular endothelium cells,
which line the blood vessels that carry the blood to the tumors.
TF has the ability to initiate the formation of blood clots
within the vessels—a process known as thrombosis. If
released in the blood vessels of tumors, the clots interrupt
the tumor's blood supply and lead to an "avalanche" of tumor
cell death, as Edgington puts it.
The key is to target this "tumor vasculature" selectively.
Since aberrant thrombosis causes both massive strokes and
heart attacks, unleashing blood clots in a general way would
be a highly dangerous approach to treating tumors—sort
of like weeding a garden with napalm.
"The [tissue factor receptor] has to land on the precisely
correct part of the tumor blood vessel cell surface," says
Edgington. He compares this to trying to land an airplane
on a narrow strip in a rainforest. The target is a tiny fraction
of the total.
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