13.02.2014

An Argentine leap forward in the fight against cancer

CONICET researchers describe a mechanism to treat some tumors resistant to conventional therapies. The paper was published in the journal cover Cell.

An Argentine leap forward in the fight against cancer

The Minister of Science, Technology and Productive Innovation, Mr. Lino Barañao and Mr. Gabriel Rabinovich, showed the cover of the journal Cell.

A new study conducted by Argentine researchers at the Institute of Experimental Biology and Medicine (IBYME-CONICET- FIBYME) promises to change the paradigm of cancer treatment and contribute to the science community in curing this disease. The study reveals the nature of one of the mechanisms of tumor resistance to certain types of cancer and the manner to reverse it. The research was published today in the prestigious scientific journal Cell as the main article included in that edition's cover. The announcement was made by the Minister of Science, Technology and Productive Innovation, Mr. Lino Barañao and Mr. Gabriel Rabinovich, director of the IBYME Laboratory of Immunopathology together with members of his scientific team.

In this regard, the head of the Ministry of Science said that “it is a very significant event, the importance of which has been highlighted by the most important cell biology journal, the journal Cell” and he added that “it is an exceptional contribution to the universal knowledge”. He also said that "it is a very important contribution, not only to the scientific sector but also for the country, because it shows another variable that should be added to the Argentine science, which has always been very efficient but now it is managing to be effective". Finally, Barañao stated that "this exemplifies the ideal of making basic science inspired in the use because it has an economic and social impact throughout the community",

To understand the research, it is necessary to understand the process by which a tumor is developed. Supply of oxygen and nutrients through the blood is essential to ensure the viability of any tissue, but it is very critical to the tumor cells that, due to their high rate of metabolism and reproduction, require higher than normal quantities. Thus, many therapies are aimed at reducing the blood supply to tumors through drugs inhibiting the proliferation of vessels in the area, along with other substances to attack tumors. However, certain tumors do not respond to anti-angiogenic treatments, i.e. those seeking to stop the creation of new vessels, and are therefore more difficult to treat.

The key lies in the relationship between two proteins: the Vascular Endothelial Growth Factor (VEGF) and the Galectin-1 (Gal-1).  Both molecules, when they act on a specific receptor of VEGF (the VEGFR2), promote the division of endothelial cells to create new blood vessels. Some anti-angiogenic drugs available on the market are specific antibodies acting as “kidnapping” the VEGF and preventing it from binding to its receptor.

"In tumors sensitive to these drugs, the antibody capturing the VEGF has positive effects. But in those resistant to these drugs, shortly after applying, a compensatory mechanism comes into scene firing the creation of vessels again" says Gabriel Rabinovich, principal researcher of the CONICET at the Institute of Experimental Biology and Medicine (IBYME, CONICET-FIBYME) and director of the work team describing this mechanism.

Rabinovich explained that after 4-5 days of giving the anti-VEGF therapy, the creation of new vessels is stopped and the oxygen levels are decreased. The group found that in refractory tumors the hypoxia activates a cascade of signals leading to the VEGFR2 'undress' of the sialic acid coating. This acid, in normal cells and sensitive tumors, acts as a 'shield' which covers the sites to which the Gal-1 can join, which is also secreted in large amounts by the tumor when the oxygen levels decrease.

Gal-1 acts on the sugars (complex N-glycan) expressing the VEGFR2 of endothelial cells, to which this interaction stimulates in order to proliferate and form new blood vessels. "In tumors sensitive to sialic acid treatment, which normally covers these receptors, remains in place. So if Gal-1 has the intention of interacting with receptors, it is impossible. However, in refractory tumors, hypoxia leading to loss of sialic acid and also increases the number of binding sites for this protein" Rabinovich says.

The research team then worked with a group of refractory tumors and managed to reverse sensitivity when giving two antibodies: one “kidnapping” a VEGF and another one “kidnapping” the Gal-1. "angiogenesis decreases after 7 days from starting the mixed treatment", says Diego Croci, CONICET assistant researcher and first author of the paper, "also, on the 4th. day we noted that the morphology of the tumor vasculature changed". Tumor blood vessels usually have chaotic and heterogeneous layouts, but with the combined therapy vessels reconfigure to resemble normal tissue. This has therapeutic benefits in two aspects: having a more orderly architecture, it has two and three times more oxygen and lymphocytes.  Then, by decreasing the levels of hypoxia the Gal- 1 production decreases and the flow of cells of the immune system to fight the tumor increases.

However, the researchers caution that although the results in laboratory and experiment animals are very positive, it is still not available for treatment. "understanding this mechanism, tumors which were previously refractory turn sensitive" Rabinovich explained, "but it is still necessary further study before given to patients".

The research received from 2010 contributions for the amount of $ 1.78 million from the National Agency for Scientific and Technological Promotion under the Ministry of Science, Technology and Productive Innovation and the CONICET, as well as support from the University of Buenos Aires, the Sales Foundation and donations from the Ferioli and Ostry family.

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The Minister of Science, Technology and Productive Innovation, Mr. Lino Barañao and Mr. Gabriel Rabinovich, showed the cover of the journal Cell.

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