|How Do Your Blood Vessels Grow?|
Ruth Levy Guyer, Ph.D.
Anything that happens about two and a half billion times must be pretty important.
That's how often your heart will beat during your lifetime. The beating pumps 1.5 gallons of blood round and round your body.
Blood travels in a series of hose-like "vessels," which range in size from the tiniest capillaries -- the smallest just wide enough to accommodate a single blood cell -- to veins and arteries of many different widths. The vessels reach into every part of the body, allowing blood to contact every cell and bathe it with oxygen and nutrients. The cells need these in order to stay alive.
The vessels that carry blood are part of the circulatory system. This system starts developing in the fetus. In adults, new blood vessels grow only under special conditions -- when a wound is being healed, when a woman is pregnant, during tumor growth, and in certain other diseases.
Tumors can grow to about 1-2 millimeters without a blood supply. But, after that, they have to link up with capillaries if they are going to grow more. Diffusion, which is how oxygen and nutrients originally got to the tumor cells, is no longer adequate to get these supplies to the tumor's interior (1).
The growth of blood vessels toward a tumor is called angiogenesis. The word comes from two Greek words, angeion, which means vessel, and genesis, which means birth. Angiogenesis is a "sprouting" process in which new vessels spring from preexisting ones. (In the fetus, vessel growth has a different name -- vasculogenesis -- and involves an entirely different mechanism) (1).
The walls of blood vessels are made of endothelial cells, cells that usually are slow to divide. Most will divide only once every few years and some only after more than 20 years. But, during angiogenesis, endothelial cells are able to meet the immediate need and divide within a few days (2). An existing vessel dissociates somewhat, endothelial cells migrate toward the tumor that is "hungry for blood," the cells divide to produce more cells like themselves, and these eventually coalesce into a new vessel (3).
Almost a quarter century ago, Judah Folkman, who is a pioneer in angiogenesis research, proposed that tumors might be stopped if angiogenesis could be stopped (4). Since that time, he and others have identified, isolated, and studied a number of substances that either stop angiogenesis or promote it.
Those substances that stop angiogenesis are called angiostatic substances (the Greek word statikos means stand, as in stand still ) (2). Those that promote it are called angiogenic factors. Some of the angiostatic and angiogenic factors are released by tumors; others are made by endothelial cells in the blood vessel walls or by cells of the immune system -- mast cells and macrophages -- that come to the site where a tumor is growing.
Folkman has proposed that the determining issue for the "success" of any tumor -- will it attract capillaries and link up with the bloodstream and grow large? -- depends on the local balance between angiostatic and angiogenic factors (5).
One of his recent discoveries is a potent angiostatic protein, conveniently named angiostatin (6). It is produced by or near a solid tumor. Angiostatin is a relatively long-lasting protein, staying in the circulation for up to 5 days. It does not normally seem to stop the growth of the primary tumor. But, as long as the primary tumor is thriving, lots of angiostatin is made and put in the circulation, and this keeps other tumors -- called metastatic tumors -- from developing elsewhere in the body.
The actions of angiostatin account for an observation that has been made both in patients and in experimental animals: often, when a primary tumor is removed, metastatic tumors pop up. When the primary tumor is removed, so is the source of angiostatin. That opens the floodgates, allowing metastatic tumors to attract blood supplies and grow.
Primary tumors produce angiogenic factors in much greater quantities than angiostatic factors. But the angiogenic factors stay in the bloodstream for only a few minutes, usually no more than four. Thus, these factors act only near the primary tumor, and they act fast. They don't travel far enough to have an influence on metastatic tumors. Only angiostatin makes it to the distant sites.
Folkman has shown that, with enough angiostatin, the growth of the mouse's primary tumor could actually be halted. Furthermore, injections of angiostatin would block growth of secondary tumors in mice whose primary tumors had been removed (6).
A blood supply allows a tumor to grow large; a blood supply also allows a tumor to spread, because it transports the cells that the tumor sheds to distant metastatic sites where the shed cells act like seeds for new tumors (7).
A substance like angiostatin (which is not just found in mice but also in humans) could turn out to be valuable as medicine. By stopping blood vessel growth, it could stop tumor growth and also the spread of tumors.
- Amer. J. Reprod. Immun. 1992, 27:171.
- J. Biol. Chem 1992, 267(16):10931
- FASEB J. 1992, 6:886.
- New England J. Med. 1971, 285:1182.
- Nature Med. 1995, 1:27.
- Cell 1994, 79:315.
- Seminars in Cancer Biol. 1992, 3:65.
This article was originally posted on the NIH electronic bulletin board EDNETon 1/16/95.