快猫短视频

IMAGINE that cancer could be treated in a similar way to diabetes, with a daily injection of a human protein that would prevent tumours from growing and spreading. Many doctors consider this prospect far-fetched. The conventional view is that patients need to be cured and cancers removed not kept at bay. But researchers at Harvard Medical School have already identified a human protein that can block the growth of tumours. And the idea is catching on fast because, unlike traditional cancer therapies, this treatment would not damage healthy tissue.

People who have been diagnosed with cancer learn to live with uncertainty. For many people, one of their worst fears is that years after a tumour has been removed, a secondary tumour will surface. Until recently, even the experts had no idea what factors dictate how fast a cancer grows, let alone what makes a secondary tumour suddenly appear. Now investigators believe the answers may lie in angiogenesis, the process that allows new blood vessels to develop.

A tumour that cannot sprout new blood vessels will not grow much bigger than a pea. And whether new vessels develop depends on a delicate balance between chemical 鈥渟timulators鈥�, or growth factors and 鈥渋nhibitors鈥�, both of which are produced by the tumour cells themselves. 鈥淎ngiogenesis is a bit like driving a car,鈥� says Judah Folkman of Harvard Medical School. 鈥淚f you think of the accelerator as a stimulator, and the brake as an inhibitor 鈥� slamming your foot on the brake stops new vessels growing.鈥�

In any tumour there will be a mix of cells 鈥� some pumping out stimulators and others making inhibitors. If the two are in balance, the tumour will remain dormant, neither growing nor shrinking. If the balance shifts so that more stimulators are produced, new vessels will develop and the tumour will 鈥渨ake up鈥� and start to expand.

This much has been known for years, but no one has yet discovered what triggers the shift. 鈥淚f we could identify how or why it happens, then we might have a way of interfering with angiogenesis,鈥� suggests Folkman. 鈥淧otentially it might be possible to harness what happens naturally, and use it to stop tumours from spreading,鈥� he says. Research in the past couple of years brings this possibility a step closer.

First, researchers led by Noel Bach at Northwestern University in Chicago discovered evidence suggesting that the process of angiogenesis is under some sort of genetic control. They found that thrombospondin, a naturally produced protein which blocks angiogenesis, seems to be controlled by a gene called p53. 快猫短视频s have known for a while that p53 normally acts to suppress tumours, because people with a mutated version of the gene are particularly prone to cancer. More recently they have shown that these people produce less thrombospondin than those who have a healthy copy of the gene.

Promising candidate

Now Folkman鈥檚 team has identified a second naturally occurring angiogenesis inhibitor called angiostatin, which normally occurs as a fragment of a blood clotting protein. 鈥淲e added angiostatin to a flask full of the sort of cells found in the walls of blood vessels and they stopped proliferating,鈥� says Folkman. Unlike thrombospondin, which has several biological functions, angiostatin appears to play just one role, making it potentially more useful as a drug.

So if angiostatin stops blood vessel growth, could it also keep cancer at bay? To find out, the team tested angiostatin on a mouse with lung cancer. The animal鈥檚 tumours stopped growing. 鈥淲e injected the mice every day, a bit like insulin injections for people with diabetes, and the tumours were held in check 鈥� preventing any further deterioration,鈥� says Folkman.

To be sure that this potent effect was caused by angiostatin the team then devised an ingenious series of experiments. They took the gene that makes angiostatin and inserted it into animal tumour cells, which they then grew in a mouse. They found that the tumours that developed from the altered cells produced a higher than normal supply of angiostatin. 鈥淭hey ended up behaving more like slow growing warts than malignant tumours,鈥� says Folkman. 鈥淎nd after three months the mouse was still going strong, which is the equivalent of about six years in human terms.鈥�

That should make angiostatin a promising candidate for treating human cancers were it not for a major snag: it is very difficult to extract angiostatin from the blood clotting protein of which it forms a fragment. Folkman reckons that it would take 3 litres of plasma and a week鈥檚 worth of laboratory time to produce just 150 milligrams, and even his mice required a dose of 1 milligram of angiostatin per day. 鈥淲e鈥檙e trying to develop alternative ways of producing it,鈥� he says. One idea is to insert the angiogenesis gene into bacteria, and let them produce the protein, but so far researchers have not been able to make this work. 鈥淲e鈥檝e tried using E. coli, but the bacteria didn鈥檛 fold the protein up properly,鈥� says Folkman.

Researchers are likely to put a lot of effort into solving this problem, because angiogenesis inhibitors act very selectively on their target. This puts them leagues ahead of other cancer therapies. The reason for such selectivity is simple, says Folkman. 鈥淎ll human cells undergo a constant cycle of renewal and turnover, but while the cells of healthy capillaries take around a thousand days to complete a full cycle, the cells of tumour capillaries take only five.鈥� Angiogenesis inhibitors act only on dividing cells, so these drugs will barely touch cells that are dividing very slowly. 鈥淗ealthy, normal vessels should be left intact, while the growth of tumour vessels should be blocked,鈥� says Folkman. Angiogenesis inhibitors appear to hold a number of other surprising advantages, too. In experiments on animals, Beverly Teicher of the Dana Faber Cancer Institute in Boston recently discovered that radiotherapy shrank tumours much more effectively when it was given in combination with angiogenesis inhibitors. This was totally unexpected, she says. Radiotherapy works best when oxygen is present to create toxic free radicals that destroy cells. 鈥淲e predicted that if we used angiogenesis inhibitors to stop new blood vessels developing, we鈥檇 reduce the flow of blood 鈥� and oxygen 鈥� to the tumour, and this would make the radiotherapy less effective,鈥� she explains. When she discovered that the opposite happened, Teicher had to rethink these ideas.

鈥淓very single prediction about angiogenesis has been proved wrong,鈥� says Folkman. 鈥淲e have to remodel our theories and come up with a new hypothesis every time we do an experiment.鈥� One plausible explanation for Teicher鈥檚 observations, he suggests, is that angiogenesis inhibitors destroy the immature tumour capillaries that tend to leak, but leave the more mature vessels intact. The result is that less fluid escapes into the surrounding tissue, and the pressure inside the tumour decreases. This encourages the surviving blood vessels to open up, allowing more blood and oxygen.

Teicher believes this theory might explain why chemotherapy, too, is more effective when given in conjunction with angiogenesis inhibitors. 鈥淚f the central vessels open up, more of the drugs will pass through and be absorbed,鈥� she says. Last year when Teicher gave a mixture of angiogenesis inhibitors and cytotoxic drugs to mice with lung tumours, she was surprised to find that almost half were cured by the cocktail. These mice were still healthy a year later 鈥� which is equivalent to about 40 years in human terms.

While this suggests that angiogenesis inhibitors have a promising future for treating human cancers, Teicher doubts that they will ever replace conventional chemotherapy. She points to experiments by Folkman, which show that tumours can be lethal even when a lack of new blood vessels means that they stay small. Folkman demonstrated this by implanting small colonies of melanoma cells along with large doses of an angiogenesis inhibitor into animal lungs. Within months the tumours filled the lungs, even though they could grow no new blood vessels. 鈥淭he tumours grew to a certain size then stopped,鈥� says Folkman. 鈥淏ut the animals still died, because the tumours carried on seeding off 鈥榙aughter鈥� tumours until the lungs were completely filled.鈥� It seems that angiogenesis inhibitors cannot always prevent secondary tumours forming.

But here again, there is other evidence that makes the picture less clear-cut. Folkman has found that angiostatin tends to build up in the bloodstream when a tumour is present, and disappears when the tumour is removed. Researchers have noticed that surgery is often followed by the rapid appearance of secondary tumours, and have presumed this happens because it changes the balance of inhibitors and stimulators. These observations suggest that some primary tumours may pump out inhibitors, and so prevent secondaries developing, though Folkman is quick to point out this does not invalidate surgery as a treatment for cancer. 鈥淥nly some tumours produce inhibitors and we have no way yet of predicting which ones do,鈥� he says.

Hit or miss

Researchers still have a long way to go before they understand how the shifting balance of angiogenesis inhibitors and stimulators affects the growth and spread of tumours. And even their efforts to stop blood vessel formation remain rather hit or miss. One approach is to test a variety of agents that might act as inhibitors. 鈥淎 few years ago we were very excited about a number of agents which seemed to prevent new vessel growth in the laboratory,鈥� says James Pluda, a senior investigator at the National Cancer Institute near Washington DC. But, when it came to clinical trials, these substances did not fulfil their promise. 鈥淣ow we鈥檙e champing at the bit for the next wave of agents,鈥� says Pluda.

One promising agent is interleukin 12, a chemical messenger whose normal function is to switch on the immune system鈥檚 white blood cells to fight infection. Another new recruit has been around for a surprisingly long time. Two years ago Bob D鈥橝mato, at Harvard Medical School, showed that thalidomide can stop blood vessels growing. Thalidomide became infamous some 30 years ago, when pregnant women who had taken it for morning sickness gave birth to children with grossly deformed limbs. Now it is being tested as an angiogenesis inhibitor. 鈥淲e don鈥檛 really know why it works, but the animal studies were very encouraging and we鈥檙e about to start the first clinical trials,鈥� says Pluda.

Recently, the effort to stop blood vessel growth in tumours has taken a new twist. Instead of trying to find substances that can inhibit the individual growth factors that stimulate development of new blood vessels, cancer scientists have begun to think more laterally about what they want to achieve. 鈥淲e鈥檙e trying to design strategies which can tackle the end-product of angiogenesis,鈥� says Pluda. 鈥淲e want to find ways of targeting the vessels themselves.鈥� One idea is to use antibodies to block the receptors that help guide growing blood vessel through the surrounding tissue. So far scientists have identified at least two such receptors on the cells of growing blood vessels, which they think would make ideal targets for this strategy. The 鈥渆ndoglin鈥� and 鈥渋ntegrin鈥� receptors work by binding to molecules in the surrounding tissue; if they are blocked by antibodies, the vessels should be stopped in their tracks.

It鈥檚 a novel approach that Philip Thorpe at the University of Texas in Dallas has taken one step further, by linking the antibodies to a toxin called ricin. The idea is that when the antibody binds to an endoglin receptor, the toxin will be in an ideal position to make a direct 鈥渉it鈥� on the vessel. One problem that Thorpe has had, however, is that the toxin can become uncoupled from the antibody before reaching the target tumour.

If experiments with these new ways of preventing blood vessel growth run according to form, they will surely uncover further complications in the process of angiogenesis. Meanwhile, Folkman is pondering another unexpected result. A few months ago one of his team took a newborn mouse with a tumour on its back, and treated it with an angiogenesis inhibitor. 鈥淲e predicted this treatment should stunt the growth of its tail, because it would need new vessels to grow, but eight weeks later the tail was fully grown and the tumour had disappeared,鈥� says Folkman. 鈥淚鈥檒l give a prize to the first person in my team who can explain this one.鈥�