Galectin- 1, a key molecule in cancer
CONICET/DICYT All evidence supports the accusation. Investigators found in different types of cancer -breast, prostate, melanoma and Kaposi’s sarcoma- that tumor cells over express Galectin-1 (Gal-1) to develop, metastasize and prevent the immune system to eliminate them. “During the last ten years we found that, in broad terms, Gal-1 favours all mechanisms associated to tumor cell growth: it allows them to escape the immune system, create new blood vessels- angiogenesis- and migrate to form metastasis”, explains Gabriel Ravinovich, principal investigator at the Institute of Biology and Experimental Medicine (IBYME, CONICET- FIBYME), and director of the investigations team.
The results obtained in their studies allowed the group to address the development of antibodies that ‘neutralize’ Gal-1, and in this way, stop the tumor’s expansion (See Monoclonal antibodies: a therapeutic answer?).
To exert its action Gal-1 binds to saccharides that cover the outer membrane of target cells and through this interaction it activates different molecular processes inside and outside the cells. “Gal-1 only acts as a messenger: when it binds to membrane saccharides it can either ‘activate’ or ‘inactivate’ cells. However, Gal-1 does not decide the effect it causes, but rather that information is codified within the membrane saccharides”, Ravinovich describes.
J. Silvio Gutkind, Chief of the Oral and Pharyngeal Cancer Branch at the National Institutes of Health (NIH), USA, explains that the studies show that “these sugars do not ‘decorate’ the cell surface, but instead they work as a code that cells use to communicate and that it can be read and deciphered by different molecules, such as galectins”.
Therefore, it is important to know that proteins such as Gal-1 are going to produce different effects depending on the membrane sugar they interact with, as this information will allow investigators to design different therapeutic approaches. Glycobiology – the study of the structure and function of saccharides and their binding proteins- is assuming greater importance worldwide. (See What is Glycobiology?).
Gal-1 and Kaposi’s sarcoma: learning about tumor angiogenesis
When a group of cancer cells begin to proliferate, they demand more nutrients and oxygen and thus need to create new blood vessels to meet this new energetic demand. This process is known as angiogenesis.
In October 2012, a study from Rabinovich’s team was published in the cover of The Journal of Experimental Medicine. In this investigation investigators describe the role of Gal-1 in angiogenesis associated to Kaposi’s sarcoma, a type of vascular tumor frequent in immunosupressed or HIV patients.
“Gal-1 binds to saccharides in the surface of endothelial cells- that form the inner layer of blood vessels- and activates them. This leads to their proliferation and spread in order to create new blood vessels”, says Diego Croci, postdoctoral fellow of CONICET at IBYME and first author of the study.
This is how the tumor manages to nourish itself and receive oxygen in order to continue growing. Nevertheless, there is one more aspect: tumor cells also use these new blood vessels to enter the bloodstream and migrate to other areas of the body to metastasize.
Gal-1 and melanoma: learning about suppression of the immune response
In 2004, an investigation published by Rabinovich’s group in Cancer Cell confirmed that tumours express and release Gal-1 as they become more invasive and more metastatic. Also, results show that these cells produce much higher concentrations of Gal-1 than normal cells.
The same team published two studies in 2007 and 2009 in Nature Inmunology, where they described the mechanisms of this pro-tumoural effect and observed that Gal-1 acts “by binding specifically to saccharides on the surface of lymphocytes Th1 and Th17, which specifically attack the tumor. Furthermore, Gal-1 adheres to dentritic cells, which are the first defence barrier and by doing so it avoids the activation of the T cells response”, Rabinovich affirms.
These effects trigger a cascade of signals that kill the lymphocytes when they are more activated and determined to attack the tumour. That is how cancer cells reduce or eliminate the body’s response oriented to destroy them and the tumour grows without being attacked by the body.
Gal-1 and prostate and breast cancer: learning about potential treatments
Apart from The Journal of Experimental Medicine, there were other two studies that appeared on the cover of Cancer Research in January and February 2013, where the investigators analysed the role of Gal-1 in prostate and breast cancer, respectively.
In the first study, Diego Laderach, Daniel Compagno and Lucas Gentilini found that Gal-1 is the galectin produced in higher concentrations by tumor cells in prostate cancer, that exploit their angiogenic role to grow and promote tumour progression.
In the second study, Mariana Salatino and Tomás D’Alotto showed that ‘silencing’ Gal-1 gene significantly reduced the growth of the tumour and the number of metastases in lungs by modulating regulatory T cells.
Monoclonal antibodies: a therapeutic answer?
Over 10 years of research at Rabinovich’s laboratory on Gal-1 and its role in cancer provided results to help investigate and develop new drugs or mechanisms to block this protein. Preliminary data proved that when Gal-1 synthesis is inhibited or the protein removed from the system, tumors cease their development and stop their metastatic process.
“The study we conducted on Kaposi’s sarcoma is the first to present specific monoclonal antibodies as an option in order to block Gal-1, and so far results have been very encouraging”, Rabinovich explains. “Although it does not cure cancer, we managed to suppress its growth and inhibit angiogenesis in 85% of cases” he adds.
According to Gutkind, to develop this type of monoclonal antibodies represents an important therapeutic advance in two senses. “It would have a dual-action: first it would inhibit angiogenesis and, second, it would increase the number of antitumor T lymphocytes, which can identify and potentially eliminate different types of cancer cells”, he concludes.
|What is Glycobiology?|
The study of sugars that are part of the cells and their extracellular matrix, their participation in the biology of the cell and their role in different diseases has acquired great relevance in the international scientific scenario.
“If we manage to comprehend the information codified in surface sugars in cancer cells and how galectines interpret these messages, we could block these interactions in processes associated to tumor progression such as the immune system escape, new blood vessels’ formation and metastatic dissemination”, Gutkind emphasises.
Croci comments that, at the same time, sugars can constitute a sort of ‘life logbook’ of the cell. “Sugars do not have a ‘mould’ such as the DNA or proteins, but instead they generate as the cell lives and its development depends on the context where it is immersed”, he stresses.
According to the investigator, the progression of normal cells to cancer cells not only depends on DNA mutations but also on the ‘cell’s lifestyle’. “That ‘experience’ translates into the membrane saccharides. They contain a lot of information that still we can’t decode and I believe that is the reason why glycobiology is becoming increasingly important, as different research teams are discovering that they bear an increasing number of different functions”, he concludes.
Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J Exp Med 2012 209:1985-2000.