Experimental models of Angiogenesis

In early experiments, researchers asked whether cancer growth requires angiogenesis. Scientists removed a cancerous tumor from a laboratory animal and injected some of the cancer cells into a normal organ removed from the same strain of animal. The organ was then placed in a glass chamber and a nutrient solution was pumped into the organ to keep it alive for a week or two. Scientists found that the cancer cells grew into tiny tumors but failed to link up to the organ’s blood vessels. As a result, tumor growth stopped at a diameter of about 1-2mm. Without angiogenesis, tumor growth stopped.

In another experiment designed to find out whether cancer growth can continue when angiogenesis occurs, researchers compared the behavior of cancer cells in two regions of the same organ. Both locations in the eye had nutrients available, but only one could support angiogenesis. Scientists found that the same starting injection of cancer cells grew to 1-2mm in diameter and then stopped in the region without nearby blood vessels, but grew well beyond 2 mm when placed in the area where angiogenesis was possible. With angiogenesis, tumor growth continued.

In an experiment designed to find out whether molecules from the cancer cells or from the surrounding host tissues are responsible for starting angiogenesis, scientists implanted cancer cells in a chamber bounded by a membrane with pores too small for the cells to exit. Under these conditions, angiogenesis still began in the region surrounding the implant. Small activator molecules produced by the cancer cells must have passed out of the chamber and signaled angiogenesis in the surrounding tissue.

Once researchers knew that cancer cells could release molecules to activate the process of angiogenesis, the challenge became to find and study these angiogenesis-stimulating molecules in animal and human tumors.

From such studies more than a dozen different proteins, as well as several smaller molecules, have been identified as angiogenic, meaning that they are released by tumors as signals for angiogenesis. Among these molecules, two proteins appear to be the most important for sustaining tumor growth: vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). VEGF and bFGF are produced by many kinds of cancer cells and by certain types of normal cells, too.

Although many tumors produce angiogenic molecules such as VEGF and bFGF, their presence is not enough to begin blood vessel growth. For angiogenesis to begin, these activator molecules must overcome a variety of angiogenesis inhibitors that normally restrain blood vessel growth.

Almost a dozen naturally occurring proteins can inhibit angiogenesis. Among this group of molecules, proteins called angiostatin, endostatin, and thrombospondin appear to be especially important. A finely tuned balance between the concentration of angiogenesis inhibitors and of activators such as VEGF and bFGF determines whether a tumor can induce the growth of new blood vessels. To trigger angiogenesis, the production of activators must increase as the production of inhibitors decreases.

The discovery of angiogenesis inhibitors raises the question of whether such molecules might therapeutically halt or restrain cancer’s growth. Researchers have addressed this question in numerous experiments involving animals. In one striking study, mice with several different kinds of cancer were treated with injections of endostatin. After a few cycles of treatment, the initial (primary) tumor formed at the site of the injected cancer cells almost disappeared, and the animals did not develop resistance to the effects of endostatin after repeated usage.

The discovery that angiogenesis inhibitors such as endostatin can restrain the growth of primary tumors raises the possibility that such inhibitors might also be able to slow tumor metastasis.

To test this hypothesis, researchers injected several kinds of mouse cancer cells beneath the skin of several mice and allowed the cells to grow for about two weeks. The primary tumors were then removed, and the animals checked for several weeks. Mice receiving no further treatment typically developed about 50 visible tumors that had spread to the lungs prior to removal of their primary tumor. But mice treated with angiostatin developed an average of only 2-3 tumors in their lungs. Inhibition of angiogenesis by angiostatin had reduced the rate of spread (metastasis) by about 20-fold.

Researchers are now asking if inhibiting angiogenesis can slow down or prevent the growth and spread of cancer cells in humans.

To answer this question, almost two dozen angiogenesis inhibitors are currently being tested in cancer patients. These inhibitors fall into several different categories, depending on their mechanism of action. Some inhibit endothelial cells directly, while others inhibit the angiogenesis signaling cascade or block the ability of endothelial cells to break down the extracellular matrix.

Date: 2015-12-24; view: 769