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Hope for Cancer Victims

Chinese scientists announced they have discovered a protein that contributes to the growth of a wide spectrum of cancerous tumors.

The protein, known as Slit, was found to have played a crucial role in forming new blood vessels that carry nourishment to the cancer cells, according to the research team, consisting of researchers from China and United States.


By cutting off such a nourishment supply to tumors, the tumors may stop growing and even regress, rendering cancer no longer the formidable killer it has been so far, the researchers said.


The discovery may prove to be a savior for the 15 million people in the world who fall victim to cancer each year, according to statistics from the World Health Organization revealed early this year.


In fact, experiments on mice with malignant melanoma, a form of skin cancer, have shown that with the blocking of the Slit-initiated blood supply, tumors stopped growing and reduced in size within weeks.


"Observations during the experiments were fairly encouraging and well matched our hypothesis that Slit plays a commanding role in the growth of blood vessels needed to support the growth of tumors," said Wang Biao, a researcher from the Shanghai-based Institute of Biochemistry and Cell Biology under the Chinese Academy of Sciences, who led the three-year research project.


In medical research terminology, the formation and growth of blood vessels that often happens in pregnancy and wound healing is called angiogenisis.


The same process occurs in tumor formation, where blood vessels grow into the tumor from the surrounding tissues.


Scientific research over the last two decades has confirmed that most solid cancers are angiogenisis-dependent.


Wang and his colleagues' discovery was published in the US-based science journal Cancer Cells late last month. Their research indicates that cancers cannot live and grow without growth of the sprouting blood vessels.


A commentary in the same issue by two world leading researchers in the field hailed this discovery as a "must-see" for peer researchers.


The Shanghai researchers found Slit, a protein previously known to play an important role in the development of the human neuronal system, is also present in a wide range of malignant tumors.


Unlike other proteins that have already been found to be able to stimulate angiogenisis, Slit is observed to be present only in the cancerous tumors while little, if any, is found in the healthy host cells.


"It gives us a strong hint that Slit is probably closely related to the growth of tumors," said Wang.


They also found the Slit protein is not evenly spread throughout the tumor, with more in the center and less on the periphery.


That reflects the proportional presence of the cancer cells in the tumor, which further strengthens the projected correlation between Slit and blood vessel formation.


Wang said it is the first time such a gradient presence of growth factors has been observed. This find could translate into better understanding of the mechanism of cancer growth and eventually the development of more efficient therapies, he added.


Dormancy therapy


This discovery has aroused a wide range of interest in the so-called "Dormancy therapy" against cancer.


That is, to treat or even cure the cancer by cutting off its blood supply and thus putting it into dormancy, rather than killing cancer cells directly using toxic chemicals or radiation.


The therapy, proposed as early as the 1970s by Dr Judah Folkman, Surgeon-in-chief at Children's Hospital in Boston, in the United States and world expert on angiogenesis, has gone through its ups and downs both in the medical community and in the press.


At one time, it was touted as the ultimate weapon against cancer that avoided the side effects typical of other commonly used therapies.


In 1996, Folkman and his colleagues found two natural compounds, angiostatin and endostatin, that shrunk tumors in mice by cutting the cancer cells' blood supply. That discovery, which was based on their continued efforts over the previous two decades, was later reported by Time magazine and finally led to a sensational New York Times front-page article in the middle of 1998 that made Folkman a reluctant hero.


A New York Times article quoted a Nobel laureate scientist as saying at that time that the therapy would be available in a practicable form "for two years.'' The scientist later denied such a saying, but the harm has already been done.


Folkman, then already known as the "father of angiogenisis," was forced to play down the disproportionate hopes brought by the new therapy following the publication of the news, saying it were still in the stage of testing on mice rather than on humans.


There have also been doubts over the efficacy of the therapy coming from within the medical community, notably from clinicians who are used to the traditional chemotherapy and radiotherapy.


Wang and his colleagues' discovery, however, comes at a time when the initial media frenzy about the therapy has subsided.


There is still serious, and ever-increasing interest in this therapy from both the industry and public research bodies.


Almost every major pharmaceutical company in the world has long-term commitments to the development of anti-angiogenisis drugs, some of which are now in the final stage of clinical trials.


Most of these drugs are designed to inhibit the growth of the so-called endothelial cells that make the lining of the blood vessels.


Scientists have found that the cancerous tumors, while growing, tend to secrete a variety of proteins, which they called growth factors, that stimulate the proliferation of endothelial cells from surrounding tissues to form new blood vessels that spread into the tumors.


A variety of drugs intended to inhibit some of the proteins are now being tested on humans.


Slit, discovered by Wang and his colleagues in Shanghai, is different in that it appears to play a directorial role in attracting the endothelial cells towards the center of the tumors rather than simply stimulating their proliferation.


"There appears to be a clear cross talk between the Slit and the endothelial cells," Wang said. "It appears that the Slit protein sends signals to endothelial cells to make them gradually grow into the tumors."


They found Slit acts by binding to another protein, known as receptor, on the endothelial cells.


They developed antibodies against the receptor, called Robo, and found they can successfully prevent it from binding to the Slit protein.


This discovery may form the basis for the development of better diagnostic measures and treatment of cancers, Wang said, but sufficient clinical trials are necessary.


"In discovering this, we used samples from up to 300 patients," he said. "To determine its use in practice, probably 10 times more patients are needed for the clinical trials."


It has been proposed, for example, that a diagnostic tool be developed to test the blood or urine of a suspected patient for any presence of Slit.


Wang said they have linked with a local hospital to carry out such trials once approval is obtained from the health authorities.


Despite all the progress that has been made in this field so far, it would also be unrealistic to pin hopes merely on the anti-angiogenisis drugs, researchers suggest.


Wang said discovery of the Slit protein suggests that there are multiple causes for the onset of cancer and therefore, a combination of a variety therapies may prove the right answer.


Folkman also proposed that the anti-angiogenisis therapy could be used in combination with chemotherapy and radiotherapy to have better effect.


The long term, more realistic goal of this therapy, he said, is to turn cancer into a chronic, manageable disease like diabetes that can be kept under control with drugs.


(China Daily August 21, 2003)



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