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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.
|Angiogenesis of a cancer (a sarcoma) in a rat. Note the chaotic pattern of blood vessels around the tumor (right) in contrast to their orderly pattern on the left. Photomicrograph courtesy of Dr. Robert D. Acland.|
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 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 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.
|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.|
Epithelial cells express transmembrane proteins on their surface — called integrins — by which they anchor themselves to the extracellular matrix.
It turns out that the new blood vessels in tumors express a vascular integrin — designated alpha-v/beta-3 — that is not found on the old blood vessels of normal tissues.
Vitaxin®, a humanized monoclonal antibody directed against the alpha-v/beta-3 vascular integrin, shrinks tumors in mice without harming them. In Phase II clinical trials in humans, Vitaxin has shown some promise in shrinking solid tumors without harmful side effects.
Clinical trials of endostatin (manufactured by recombinant DNA technology), in combination with standard chemotherapy have shown some benefit in one type of lung cancer.
Bevacizumab (Avastin®). This is a humanized monoclonal antibody that binds to VEGF thus keeping it from binding to its receptors. Approved by the US FDA in February 2004 for the treatment of colorectal cancers.
Ranibizumab (Lucentis®) is a modified version of Avastin® that is showing great promise in inhibiting the formation of new blood vessels in the retina — the cause "wet" macular degeneration.
Trials are also scheduled to begin on a synthetic ribozyme that blocks synthesis of the VEGF receptor.
These are only a few examples of the ~50 antiangiogenesis drugs now in clinical trials.
In animal studies, some cancers — notably pancreatic cancer — have turned out to resist chemotherapy because of their poor blood supply. Perhaps such cancers need to have angiogenesis promoted; inhibiting it could make a bad problem worse.