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Mariño, K.V., Cagnoni, A.J., Croci, D.O. et al. Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov 22, 295–316 (2023). https://doi.org/10.1038/s41573-023-00636-2
Galectins are proteins that bond to glycan, a carbohydrate-based molecule created by all living organisms. These proteins change the functions of cells. A variety of strategies for targeting galectins to aid in cancer, fibrosis, and hepatitis are currently being researched.
One way targeting galectins fights cancer is through glycan remodeling, the changing of glycans. This remodeling is controlled by enzymes. When glycans are altered, it affects processes such as cellular communication (cells speaking to one another), proliferation (creation of more cells through cell division), differentiation (cells turning into their mature forms), and survival. When this occurs in cancer cells, it can affect cell adhesion (the ability of cells to stick to one another), epithelial-to-mesenchymal transition (cells that cover the insides and outsides of body surfaces changing into cells that cells of connective tissues in the body), angiogenesis (the formation of new blood vessels), immunoediting (transformation of cells to cancer), and metastasis (the spread of cancer cells past where it originated in the body). All these processes can significantly contribute to the worsening of cancer, and hence, being able to have an effect on them is of incredible use.
Additionally, targeting galectins also works to combat fibrosis, which is the formation of connective tissue when injury or damage occurs to the body. When tissues regenerate, scars form because of a larger than normal presence of collagen deposited through fibroblasts (a cell that helps produce connective tissue), epithelial cells, endothelial cells, and macrophages (a white blood cell that helps the body fight pathogens and microorganisms). On the genetic level, the gene GAL3, which encodes a protein that supports macrophages that cause fibrosis, is unregulated, meaning that it produces without anything stopping it. Notably, research has found that in mice, when GAL3 is regulated, the fibrosis reduces in severity. For GAL3, endothelial cells and myofibroblasts (a type of cell with stress fibers composed of actin protein bundles) increase the expression of GAL3 which leads to cell processes like epithelial-mesenchymal transition, apoptosis (cell death), myofibroblast proliferation, and fibronectin (a type of glycoprotein) production.
Currently, research on galectin targeting has been focused on finding strategies with the knowledge known about its role in cancer and fibrosis. One such strategy is small-molecule carbohydrate inhibitors. Cell expression can be prevented through inhibitors, which bind to DNA and prevent DNA from eventually being made into proteins. In galectins, scientists originally attempted to bind carbohydrates such as LacNAc to the galectins to repress gene expression, but the binding had a low affinity (attraction) and the carbohydrates were quickly degraded by glycosidases, enzymes that break down the carbohydrates. This method was improved by making modifications to the carbohydrates to improve their affinity to binding to galectins, but the carbohydrates were still quickly degraded.
Another method being researched is one involving the use of polysaccharides and their derivatives. The polysaccharides that were derived from pectins, a group of polysaccharides found in cell walls, have shown antitumor, antimetastatic, and anti-inflammatory abilities. Modified citrus pectins, found in citrus fruits, make galactose more accessible in cells, increasing the affinity for inhibitors to bind to galectin. In a clinical trial of one polysaccharide derivative, there was shrinkage of over 50% in lymph node lesions in 16% of patients. Another pectin-derived compound, belapectin, was able to decrease tumor growth in 50% of patients with metastatic melanoma!
In conclusion, anti-galectin therapies are a growing field of research to combat cancer and fibrosis, having promising prospects for treatment in the future.
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