Fighting Cancer with Angiogenesis Inhibitors

Once a nest of cancer cells reaches a certain size (1 -2 mm in diameter), it must develop a blood supply in order to grow larger. Diffusion is no longer adequate to supply the cells with oxygen and nutrients and to take away wastes.

Cancer cells (probably like all tissues) secrete substances that promote the formation of new blood vessels - a process called angiogenesis.

Over a dozen substances have been identified that promote angiogenesis. A few examples are:

angiopoietin-1
basic fibroblast growth factor (bFGF)
vascular endothelial growth factor (VEGF).

Curiously, some tumors, at least, also secrete substances that inhibit angiogenesis. This explains a clinical phenomenon that has been known for decades:

A patient has a tumor, the so-called primary tumor.
There is no evidence that the primary tumor has metastasized.
A surgeon removes the primary tumor.
Some weeks later metastases of the tumor appear throughout the patient's body
The speed of their appearance indicates that they were present all along but too small to be detected.

This phenomenon caused Dr. Judah Folkman of Children's Hospital and the Harvard Medical School in Boston to hypothesize that a large primary tumor secretes not only stimulators of its own angiogenesis but angiogenesis inhibitors that are released into the circulation and inhibit angiogenesis - and thus further growth - of any metastases of the primary tumor.

A number of inhibitors of angiogenesis have been discovered.

Angiostatin

Angiostatin is a polypeptide of approximately 200 amino acids. It is produced by the cleavage of plasminogen, a plasma protein that is important for dissolving blood clots. Angiostatin binds to subunits of ATP synthase exposed at the surface of the cell embedded in the plasma membrane. (Before this recent discovery, ATP synthase was known only as a mitochondrial protein.)

Endostatin

Endostatin is a polypeptide of 184 amino acids. It is the globular domain found at the C-terminal of Type XVIII (18) collagen (a collagen found in blood vessels) cut off from the parent molecule.

Biological effects of angiostatin and endostatin in mice

In mice,

Injections of angiostatin inhibit the metastasis of certain (mouse) primary tumors.
Injections of endostatin (made by recombinant DNA technology) cause the primary tumor to regress.

In time, the primary tumor reappears, but

a repeat injection causes it to regress again.

Each time it reappears, the tumor is just as susceptible to treatment as before.

This is not seen with conventional chemotherapy. Repeated exposure to chemotherapeutic drugs selects for the appearance of drug-resistant tumor cells. Eventually, further drug treatment is worthless. Why the difference in response? Chemotherapy works directly on tumor cells which mutate easily. Angiogenesis inhibitors don't work on the tumor cells but on normal cells involved in the formation of blood vessels.

After a few cycles of growth, treatment, and regression, the primary tumor finally stops growing (at least in the cases examined) and remains dormant at a small size.

Some human tumors can be grown in immunodeficient mice. (Being immunodeficient, they cannot reject this foreign tissue). Treatment with endostatin caused these human tumor masses to shrink in their mouse host.
Combined treatment with both angiostatin and endostatin has caused some primary mouse tumors to disappear entirely.

Endostatin also blocks the build-up of plaque (in mice)

Endostatin also inhibits the development of the fatty deposits - called plaque - in the aorta of mice. The cells within plaque need a capillary supply and endostatin blocks its formation - at least in mice. If it works in humans, it might be helpful in preventing atherosclerosis - a primary cause of strokes and heart attacks.

Troponin I

This protein is a component of muscle. However, in soluble form it appears to be even more potent at inhibiting angiogenesis than angiostatin and endostatin.

Prostate Specific Antigen (PSA)

This protein is produced in elevated amounts in men with prostate cancer, and measuring PSA levels is used to screen for this cancer. However, despite its name, it is also associated with other cancers, e.g., breast cancer. Workers at EntreMed, the firm that is manufacturing Endostatin, have found that PSA is an angiogenesis inhibitor and reduces tumors in mice. Perhaps elevated levels of PSA are a reflection of the body's own attempt at controlling tumors.

Synthetic angiogenesis inhibitors

Epithelial cells express transmembrane proteins on their surface - called integrins - by which they anchor themselves to the extracellular matrix (at patches called desmosomes).

It turns out that the blood vessels in tumors express a vascular integrin - designated anb3 - that is not found on the blood vessels of normal tissues. A monoclonal antibody directed against the anb3 vascular integrin shrinks tumors in mice without harming them.

What does the future hold for angiogenesis inhibitors?

Phase I clinical trials of endostatin are scheduled to begin this year now that sufficient quantities are being manufactured (by recombinant DNA technology). Development of angiostatin is taking longer. Let's hope that endostatin, at least, proves as safe and effective in humans as it has in mice.

Phase I and Phase II trials are now complete for Vitaxin, a humanized monoclonal antibody against the vascular integrin anb3 (see section above). It has shown some promise at shrinking solid tumors and only minor side effects.

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6 October 1999