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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Professor Thomas S. Edgington and members of his laboratory in the Department of Immunology have been working on blocking the flow of blood to a tumor. Photo by Biomedical Graphics.