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prevent the tumor from crossing the border

Israeli researchers discovered how cancerous tumors manage to metastasize and develop blood vessels around them. They also managed to prevent the process, meanwhile in the laboratory

Merit Sloin

Cancerous tumors are trouble. Cancerous tumors that have developed around them
Blood vessels or metastases are a bundle of trouble. The attempts to find ways
Preventing the crops from doing this has been a source of income for researchers for many years
and laboratories around the world. At the end of last week progress was made
significant in the field, when the work of a research group was published
Israeli. The researchers, from Hadassah Ein Kerem Medical Center and co
"Insight" in Rehovot discovered that his enzyme plays a central role in the process
The formation of metastases and blood vessels around the tumors. They also isolated the garden
who is responsible for creating the enzyme and managed to produce antibodies that recognize it.
The discoveries open the door to new diagnostic and treatment approaches for cancer
and other diseases in which the enzyme is involved.

The cancerous tumors have developed sophisticated tactics that enable them
multiply and spread to the organs of the body. For example, in order to create
Metastases penetrate the cancer cells into the blood vessels and migrate through them to
target organs; When they arrive, they have to get out of the blood vessels, penetrate into
the organ and create metastases. This is not a simple task: inside the blood vessels
The cancer cells expect a preventive attack from the cells of the immune system. also streamed
The blood does not benefit them, since within the tumor they are supported and held on
in neighboring cells. To survive and succeed in reaching their destination on the cells
stay in the blood vessels for only a short time, less than three hours. and also
Thus, only one out of every thousand cancer cells succeeds in making the journey.
But a single cell is enough to form a cancerous tumor.

One of the sophisticated mechanisms is the one by which cells succeed
The cancer penetrates through the blood vessel wall, once at the entrance and once at the exit.
Cell movement begins in the small blood capillaries. The capillary wall is covered
on its inner side in a layer of cells called endothelial cells. these cells
An additional layer is produced on the outside of the capillary wall, a "membrane."
basalt" her name. This membrane is the main barrier we face
The cancer cells when they detach from the original tumor and when they come out
out of the bloodstream. Researchers knew that somehow the cells were successful
Cancers subdue one of the components of the membrane - sugar chains
long, called "paran-sulfate" - and penetrate into the bloodstream.

In 1983, Prof. Israel Volodevsky, from the research unit, decided
The biology of cancer at the Hadassah Ein Kerem Medical Center, search the
The substance that helps cancer cells penetrate and exit the blood vessels. "I assumed
that there must be some enzyme that cuts or dissolves the chains
the sugars, and gives the cancer cells the aggressive invasiveness
that characterizes them", he says. He and his team were raised in Thai culture
endothelium. After the endothelial cells produced a basal membrane, they tested
The process of penetration of malignant cells through the membrane. in research
The enzyme that allows cancer cells to break down the
Heparan sulfate. It was also found that the enzyme, the enzyme he named, is produced and secreted
in large quantities precisely by cancer cells with metastatic potential

And Ludavsky therefore turned to test the enzyme in humans. He found
the enzyme ferrase in the urine of patients with metastatic diseases, but no
in healthy people. The research team began trying to develop inhibitors
to the enzyme with the aim of inhibiting the spread of malignant tumors
in laboratory animals. The results were surprising: the inhibitors were able to lower
the number of metastases by 90% but that was not enough. in the mice
who were treated with inhibitors, many side effects were found.

The only way to proceed was to try to isolate the farnase enzyme,
to find the sequence of amino acids that make it up and hence isolate the
The gene responsible for creating the enzyme. This data might help
For them to understand how gene activity is regulated, to create the enzyme
in large quantities and develop effective inhibitors against it. "At this point
We were stuck for at least five years," Volodevsky recalls. "We succeeded though
to isolate the enzyme, but we did not arrive at deciphering the molecular sequence

About a year and a half ago, Volodevsky met with Dr. Dror Melamed and Dr
Iris Packer from Insight, in the Rabin Science Park
in Rehovot, specializing in the development of molecular methods for expression and activation
Gardens. By scanning gene libraries and sophisticated techniques
For protein purification and expression, the researchers were able to characterize the gene
which is responsible for the creation of the enzyme paranase. It turned out to be a unique garden
which was not known until then, and is the first gene known to produce it
An enzyme that breaks down polysaccharides from the heparan sulfate family. company
"Insight" and Hadassah registered a patent on the gene, on its structure, on the enzyme
which it codes and its clinical uses. The patent was approved
in the USA.

It was also found that the enzyme is first produced in a dormant form, and only later
Another enzyme appears, unknown, which activates it. Volodevsky: "Now
They are trying to characterize the enzyme that converts the enzyme from its dormant form
to its active form. This way we can control the expression level of the enzyme
and develop effective inhibitors against it."

After the gene coding for the enzyme Fernase was isolated, Dr. Tovia succeeded
Peretz from the Insight company to produce antibodies for him. The antibodies can not
Just to inhibit the enzyme and serve as a medicine, but also to serve as a means
To diagnose tumors with a high metastatic potential. Indeed, through
The antibodies found that in human tumors that are prone to develop metastases,
The enzyme is found in relatively large quantities. Volodevsky: "The premise
Ours was correct. We found the Franz in invasive breast cancer and not in the tissue
normal breast The same goes for liver cancer, colon cancer, and more." now
The researchers are developing a method that will make it possible to identify, using the antibodies,
Metastatic diseases in their early stages by identifying quantities
Small amounts of the enzyme in urine and plasma.

In an article published last Thursday in the cover story of the scientific monthly
In Nature Medicine, the researchers also report on experiments they did
in mice, where they injected the gene into non-sending cancer cells
metastases After inserting the gene, the cells became metastatic and the mice
died in a short time. "Apparently this is a key enzyme in the process
Creating the metastases," says Volodevsky.

Laboratory research currently underway shows that the enzyme plays an important role
In another basic field in the biology of cancerous tumors. known
It is because the cancerous tumor releases substances that accelerate vessel growth
blood around him. The proliferation of blood vessels in the tumor area allows for material delivery
Food and oxygen for cancer cells. Without them, the tumor does not develop.
A few years ago, Volodevsky and his team found that the substances that stimulate
New blood vessel growth is closely related to heparan sulfate.
And Ludavsky: "Wherever the parasulphate exists, we found that it is
Connected to factors that stimulate blood vessel growth. for a tool to be created
blood, a certain enzyme should release them from the state in which they are stored
in the extracellular material. The one who performs the work is the enzyme Franz."
In the experiments it became clear that heparanase is not only involved in cancer. he
Responsible for both migration of white blood cells to areas of inflammation and migration
Immune system cells that attack self-tissues in diseases

"Insight" company has developed infrastructures for scanning and discovery of materials
Fernase inhibitors, which may be used in the future as drugs for cancer, inflammation
and autoimmune diseases. It also develops the inhibitory antibodies
The franz as remedies for these diseases.

© Published in "Haaretz" on 04/07/1999

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