IBYME
From laboratory to treatment: Galectin- 1, a key molecule in cancer
The protein is produced in large amounts by tumours to form new blood vessels and eliminate antitumor immune defenses to grow and spread. To block Gal-1 may result in a therapeutic alternative to suppress angiogenesis and potentiate cancer-specific immune responses.
All facts support the allegation. A group of researchers found in different types of cancer –including breast, prostate, melanoma and Kaposi’s sarcoma- that tumor cells over express Galectin-1 (Gal-1), a sugar-binding protein, to grow, form new blood vessels, metastasize and prevent their elimination by the immune system.
“During the past ten years we found in general that Gal-1 favours different mechanisms associated to tumor cell growth: it allows cancer cells to escape the immune system, create new blood vessels- a process termed angiogenesis- and migrate through these vessels to form metastasis”, explains Gabriel Ravinovich (director of the team) and principal researcher at the Institute of Biology and Experimental Medicine (IBYME, CONICET- IBYME) and the Department of Biological Chemistry, Faculty of Exact and Natural Sciences, University of Buenos Aires.
The results obtained in their studies allowed the generation of a panel of monoclonal antibodies that ‘neutralize’ Gal-1, and in this way, stop the tumor cell 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 this lectin activates different molecular processes inside and outside the cells. “Gal-1 acts as a messenger: when it binds to membrane saccharides it can either ‘activate’ or ‘de-activate’ cellular processes. However, Gal-1 does not decide the fate of the cells alone; this outcome also depends on the biological information encrypted by cell surface saccharides”, Rabinovich states.
J. Silvio Gutkind, Chief of the Oral and Pharyngeal Cancer Branch at the National Institutes of Health (NIH), USA, explains that these studies show that “sugars do not ‘decorate’ the cell surface, but instead they function as a code that cells use to communicate each other and that can be read and deciphered by different molecules, such as galectins”.
Therefore, it is important to understand how glycan-binding proteins such as Gal-1 are committed to produce different effects depending on the cell surface sugar with which they interact, as this information will allow investigators to design different therapeutic approaches. Glycobiology – the study of the structure and function of saccharides and their binding partners- is acquiring great importance worldwide. (See What is Glycobiology?).
Gal-1 and Kaposi’s sarcoma: learning about tumor angiogenesis
When a group of cancer cells start to proliferate, they require more nutrients and oxygen and need to create new blood vessels to meet this new energetic demand. This process is known as angiogenesis.+ç
In October 2012, a study from Rabinovich’s team was published in the cover of The Journal of Experimental Medicine. In this study the authors describe the role of Gal-1 in angiogenesis associated to Kaposi’s sarcoma, a type of vascular tumor frequent in immunosupressed or untreated HIV-infected patients at late stages of the disease.
“Gal-1 binds to saccharides in the surface of endothelial cells- that form the inner layer of blood vessels- and activates these cells. This process 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 the way tumors manage to nourish themselves and receive oxygen in order to continue growing. Nevertheless, there is one more critical aspect: tumor cells also use these new blood vessels to access the bloodstream and migrate into other target tissues to generate metastasis.
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 to evade the immune response.
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 “through binding specifically to saccharides on the surface of Th1 and Th17 lymphocytes, which are responsible of attacking the tumor but can also induce autoimmune responses. Furthermore, Gal-1 binds to dendritic cells, which are the first defense barrier and by doing so it avoids the activation of the T cells”, Rabinovich says.
This effect triggers a cascade of signaling events which enables killing oflymphocytes when they are more activated and determines tumor attack. This is the way how cancer cells thwart or eliminate the body’s immune defenses.
Gal-1 and prostate and breast cancer: learning about potential treatments
In addition to the study published in The Journal of Experimental Medicine, two other studies that appeared on the cover of Cancer Research in January and February 2013, report the major role of Gal-1 in prostate and breast cancer, respectively.
In the first study, Diego Laderach, Daniel Compagno and Lucas Gentilini analyzed the lectin signature of these cells and found that Gal-1 is the most relevant galectin produced at higher concentrations by tumor cells in prostate cancer, and tumor cells exploit its pro-angiogenic activity to grow.
In the second study, Mariana Salatino and Tomás D’Alotto Moreno showed that ‘silencing’ Gal-1 gene significantly reduced the growth of the tumour and the number of metastases in lungs by modulating a particular type of T cells called regulatory T cells.
Monoclonal antibodies: a therapeutic strategy to block Gal-1?
Over 10 years of basic research at Rabinovich’s laboratory on Gal-1 and its role in cancer supported the development of new drugs to block this protein in the tumor microenvironment. Preliminary data proved that when Gal-1 synthesis is inhibited or the protein is removed, tumors stop their growth and interrupt their metastatic process.
“The study we conducted on Kaposi’s sarcoma is the first to present specific monoclonal antibodies as a therapeutic option in order to block Gal-1, and so far results have been encouraging”, Rabinovich explains. “Although it does not cure cancer, we managed to suppress its growth and inhibit angiogenesis in 85% of cases.
According to Gutkind, development of 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 glycans (sugars) that are vital components of the cells and their extracellular matrix, their role in the biology and their implications in different diseases has acquired great importance in the international scientific scenario.
“If we manage to understand the information encoded by cell surface sugars in cancer cells and to understand the way how galectins interpret these messages, we would be able to block these interactions in processes associated to tumor progression such as tumor-immune escape, formation of aberrant blood vessels and metastatic dissemination”, Gutkind emphasizes.
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 their development depends on the context where they are immersed”.
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 bulk of information that we still cannot decode. This is the main reason why glycobiology is becoming more and more exciting, as different research teams are discovering that glycans display an important number of different functions”, he concludes.
References
Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J Exp Med 2012 209:1985-2000.
Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection. Cancer Cell, Volume 5, Issue 3, 241-251, 1 March 2004.
Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nature Immunology 10, 981 – 991 (2009).
Differential glycosylation of TH1, TH2 and TH-17 effector cells selectively regulates susceptibility to cell death. Nature Immunology 8, 825 – 834 (2007).
Targeting Galectin-1 Overcomes Breast Cancer-Associated Immunosuppression and Prevents Metastatic Disease. Cancer Res; 73(3); 1107–17.
A Unique Galectin Signature in Human Prostate Cancer Progression Suggests Galectin-1 as a Key Target for Treatment of Advanced Disease. Cancer Res; 73(1); 86–96.
- By Ana Belluscio.