It is possible that the experimental drugs to "starve" cancer tumors do not take into account another mechanism for creating blood vessels used by the tumors
By Uri Nitzan
Photo: Lior Mizrahi
Prof. Jacob Parr and a patient. Partner in the discovery of the protein that stimulates the formation of blood vessels in intraocular tumors In the last decade, a new strategy for curing cancerous tumors is taking shape. Every tumor needs oxygen and food, just like healthy tissues, and in early stages it receives the same blood vessels in its immediate environment. The tumor's oxygen consumption increases in direct proportion to its volume, and at a certain point the malignant mass already needed its own blood vessels. The development of the ability to suppress, and alternatively encourage, the production of blood vessels has become a major research goal in biology, in the hope that a way will be found to starve malignant tumors and thus stop their spread.
The process of making blood vessels is called angiogenesis, and many researchers have already identified some of the important proteins involved in this process. The VEGF protein is one of the main players in the angiogenesis process, and its main site of action is the endothelial cells lining the blood vessel wall. Apparently, binding of VEGF to receptors on the endothelial cells induces a chain of intracellular reactions, cell proliferation and accelerated development of new blood vessels.
Pharmaceutical companies and many angiogenesis researchers believe that precise damage to the endothelial cells is the key to destroying tumors: damage to the endothelial cells will destroy the blood vessels that supply oxygen to the tumor, prevent metastatic spread and ultimately starve the tumor to death. Thus, experimental drugs target receptors on endothelial cells or proteins such as VEGF that bind to those receptors. The new drugs arouse great expectations among scientists and patients. Cancer patients are already receiving the drugs in clinical trials, but their effectiveness has not yet been proven.
Prof. Jacob Parr, director of the ophthalmology department at Hadassah Ein Kerem Hospital, researches and treats tumors in the eyes, and every year several dozen patients who suffer from "melanoma of the iris" come to him. The uvea is located inside the eyeball, between the sclera and the retina, and its main function is to supply blood to the retina.
"It is common to think that the walls of blood vessels are lined exclusively with endothelial cells," says Parr, "but during the characterization of the blood vessels of the melanoma tumor, we were surprised to find that the tumor cells produce channels for blood transport even without the involvement of endothelial cells." This discovery has significant implications for the potential target cells of drugs that inhibit angiogenesis. These drugs home in on endothelial cells, and their effectiveness will decrease in tumors where malignant cells integrate into the wall of the blood vessels and function like the endothelium. "Many researchers find it difficult to accept our findings", says Parr, "because the possibility that melanoma cells are able to function like endothelial cells and produce channels for blood transport is a deviation from the accepted paradigm in the study of angiogenesis". The degree of generality of the phenomenon is still unclear, and the dispute is sharpening against the background of the fact that similar findings have not been discovered in other tumors.
The interest in vascular development of tumors also led Farr to the identification of proteins involved in intraocular angiogenesis. Dense growth of blood vessels accompanies many intraocular diseases. In all these diseases, the retinal tissue suffers from a lack of oxygen, and the increased formation of blood vessels is seen as a natural response to this deficiency. The protein responsible for intraocular angiogenesis, whose identity was unknown for a long time, was called factor X. Prof. Eli Keshet from the Hebrew University studied and characterized the protein VEGF. Keshet showed, among other things, that the production of VEGF in cultured cells increases in response to a lack of oxygen and decreases in situations of excess oxygen. Working together, Prof. Parr and Prof. Keshet were able to show that factor X, which induces intraocular angiogenesis, is the same as the VEGF protein.
Later, other eye diseases characterized by a lack of oxygen supply to the retina and dense angiogenesis within the eye were studied. Overexpression of VEGF is found in common diseases such as ocular diabetes, retinal vein occlusion and retinopathy of prematurity. The revelation of the identity of Factor X was first published in 1995 in the journal "Investigations. "Laboratory
"Melanoma of the grape", during the research on which Farr and his partners discovered that the cancer cells function like the endothelial cells, is a rare tumor, and it is also unknown among doctors. "The source of the malignant tumor is the melanocyte cell. In a healthy eye, the melanocytes absorb unnecessary light that penetrates the eye," says Prof. Farr. "The transition to malignancy is the result of a sequence of mutations in the hereditary material of a single cell.
The defective melanocyte divides uncontrollably, the cancerous mass is formed, and eventually the malignant metastases are also sent."
Today it is common to treat "melanoma of the grape" using radioactive substances, but many patients come to the doctor late. The diagnosis of the tumor is made after metastases have been sent to the liver, and doctors are no longer able to help patients. The metastases are sent to the general blood system through the tumor's unique blood vessels, from where they are carried to the liver. It will be possible to treat metastatic spread using the experimental anti-angiogenic drugs, which are supposed to damage the blood vessels of the tumor; But Prof. Farr and his partners are convinced that in the case of the "melanoma of the grape" the blood vessels of the tumor will not respond to drugs directed only against the endothelial cells.
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