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Cancer Biology

The Molecular Perspective: Tissue Factor

The Scripps Research Institute, Department of Molecular Biology, La Jolla, California, USA

Correspondence: David S. Goodsell, Ph.D., Associate Professor, The Scripps Research Institute, Department of Molecular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Telephone: 858-784-2839; Fax: 858-784-2860; e-mail: goodsell{at}scripps.edu Web site: http://www.scripps.edu/goodsell

Received June 19, 2006; accepted for publication June 19, 2006.

	LEARNING OBJECTIVE

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After completing this course, the reader will be able to:

1. Discuss tissue factor and its role in metastasis.
   

Blood clotting is a delicate business that must be carefully controlled. The blood must be ready to clot at a moment’s notice since damage can occur at any time. But it must clot just enough to stanch the flow of blood at the wound but not anywhere else in the body. Many deadly diseases with sudden onsets are disorders of blood clotting, including hemophilia, heart attack, and stroke. It is becoming clear that metastasis also has close ties with blood-clotting machinery.

The circulatory system uses a very simple method to locate wounds quickly and precisely. Cells in the neighborhood around blood vessels have tissue factor on their surfaces, whereas cells inside the vessels do not. Most of the time, the blood flows normally through the vessels and never comes into contact with tissue factor. But when the vessel is broken, blood flows out and finds tissue factor on epithelial or muscle cell surfaces. This is the signal that something is wrong.

A cascade of protein activation is used to build the clot. One pathway starts with tissue factor, which activates factor VII, which then activates factor X, which activates thrombin, which finally activates the fibrin that forms the clot (Fig. 1, Fig. 2). Two tricks are employed in this cascade to build a perfect clot. First, each step in the cascade activates many copies of the next step. This allows the small signal from a few tissue factor molecules to be amplified into the activation of many fibrin molecules. The second trick is that these proteins are very unstable when activated, so they don’t diffuse very far from the wound and the clot stays localized just where it is needed.

In recent years, research has shown that tissue factor plays more than just this passive role as trigger. It is tied to cell signaling processes that activate the machinery needed for cell growth and mobility. The details are complex and dependent on the cell type, but the complex of tissue factor with factor VII is a key element in initiating the signaling events, either by directly signaling through tissue factor or by together activating a neighboring cell receptor.

This role in cell signaling makes tissue factor a player in metastasis of cancer cells. When cancer cells metastasize, they must overcome many cellular hurdles as they break away from the tumor, travel through the blood, and take up residence in a distant part of the body. The signals sent by tissue factor can assist tumor cells by promoting many processes that are normally inhibited in healthy cells. These include enhanced growth of blood vessels in the neighborhood and inhibition of apoptosis.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The author indicates no potential conflicts of interest.

View larger version (62K): [in this window] [in a new window]   Figure 1. Tissue factor is a sausage-shaped protein that extends from the cell surface. A short tail links it to the membrane and may be involved in signaling inside the cell. Factor VII, the next player in the coagulation cascade, is a long, snaky protein that wraps around tissue factor. This activates the factor so that it becomes a protease. It will then make a specific cut in factor X, activating it and allowing it to make a specific cut that activates thrombin. Factors VII and X coordinate several calcium ions, shown in yellow, using a collection of modified glutamic acids, shown in bright red. These ions help tether the factors to the cell membrane. Atomic coordinates were taken from entries 1dan, 1xka, 1iod, and 1ppb at the Protein Data Bank (http://www.pdb.org).

View larger version (88K): [in this window] [in a new window]   Figure 2. Hemostasis in action. In this cross section, tissue factor (bottom center, on the surface of the cell on the right) has triggered a cascade in the blood serum leading to formation of fibrin fibrils (in red, filling the space at the top).

	FURTHER READING

Top Learning Objective Disclosure of Potential... Further Reading

Versteeg HH, Spek CA, Peppelenbosch MP et al. Tissue factor and cancer metastasis: the role of intracellular and extracellular signaling pathways. Molecular Medicine 2004;10:6–11.[CrossRef][Medline]

Robert HR, Monroe DM, Hoffman M. Molecular biology and biochemistry of the coagulation factors and pathways of hemostasis. In: Williams Hematology, Seventh Edition. McGraw-Hill, 2006.

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