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Galectins Sebagai Modulator Progresi Tumor

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Galectins (juga dikenal sebagai galaptins atau S-lectin) merupakan famili lektin yang terikat pada beta-galactoside. Famili ini dikenal dengan setidaknya satu karakteristik carbohydrate recognition domain (CRD) dengan afinitas untuk beta-galactosides dan berbagi sekuen elemen tertentu.

Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology?

The Galectin family

a | Galectins are a family of animal lectins characterized by conserved carbohydrate-recognition domains (CRDs) consisting of about 130 amino acids that are responsible for carbohydrate binding. So far, 15 mammalian galectins have been identified. They can be subdivided into three groups: those containing one CRD (galectin-1, 2, 5, 7, 10, 11, 13, 14 and 15); those containing two distinct CRDs in tandem, connected by a linker of up to 70 amino acids (galectin-4, 6, 8, 9 and 12); and galectin-3 (Gal-3), which consists of unusual tandem repeats of proline- and glycine-rich short stretches (a total of about 120 amino acids) fused onto the CRD. There are different isoforms of two-CRD type galectins, and these vary with respect to the length of the linker.

b | Many galectins are either bivalent or multivalent with respect to their carbohydrate-binding activities: some one-CRD galectins exist as dimers; two-CRD galectins have two carbohydrate-binding sites; and galectin-3 forms oligomers when it binds to multivalent carbohydrates. Galectins can interact with cell-surface glycoconjugates, some of which are transmembrane proteins. Galectins can crosslink some of these glycoconjugates and trigger a cascade of transmembrane signalling events. Although binding to only two glycocoproteins is shown here, galectins can potentially cause the clustering of multiple multivalent glycoconjugates, resulting in a lattice formation. They can also bridge two cells of the same or different types, and bridge cells to extracellular matrix proteins. For simplicity, saccharides recognized by galectins are shown here as disaccharides, but they are likely to be oligosaccharides. In addition, the different colours of the saccharides shown here reflect the fact that different galectins bind to different sets of oligosaccharides.

Intracellular and extracellular functions of galectins

Galectins (shown here as Gal-1–Gal-12) can be intracellularly located or secreted into the extracellular space. Extracellularly, they can crosslink cell-surface glycoconjugates that are decorated by suitable galactose-containing oligosaccharides and can deliver signals inside the cell. Through this mechanism, they modulate mitosis, apoptosis and cell-cycle progression. Intracellularly, galectins shuttle between the nucleus and cytoplasm and are engaged in fundamental processes such as pre-mRNA splicing. They can also regulate cell growth, cell-cycle progression and apoptosis by interacting with the relevant intracellular signal-regulation pathways. Although the galactosyl ligands recognized by galectins have been drawn to be the same in this figure, galectins have high specificity for oligosaccharides, and each can bind to a different set of glycoconjugates. Also, although we have not explicitly shown them here, galectins can bind to both glycolipids and glycoproteins.

Roles of galectins in tumorigenesis

Galectins might have important roles during different steps of tumorigenic processes, including tumour cell transformation, cell-cycle regulation and apoptosis. a | Galectin-1 (Gal-1) and Gal-3 can mediate neoplastic transformation by interacting with oncogenes, such as oncogenic Ras (HRAS and KRAS shown here), and promote Ras-mediated signal transduction (shown here to involve RAF1, extracellular signal-regulated kinase (ERK) 1/2, phosphatidylinositol-3-kinase (PI3K) and the serine/threonine kinase AKT). b | Galectins can also control tumour progression by modulating cell-cycle progression. In particular, Gal-3 regulates the levels of known cell-cycle regulators (including cyclin A, E and D), as well as the cell-cycle inhibitors p21 (WAF 1) and p27 (KIP1), resulting in cell cycle arrest. Gal-1 and Gal-12 induce arrest at various stages of the cell cycle, although the molecular mechanisms of this have not been elucidated. c | Galectins regulate apoptosis. Gal-1 and Gal–9 can induce tumour cell apoptosis when added exogenously to the cell, whereas Gal-7 and Gal-12 promote apoptosis through intracellular mechanisms. Gal-3 has anti-apoptotic functions and it translocates to the perinuclear membrane and to the mitochondria in cells exposed to apoptotic stimuli. The translocation is dependent on synexin, a phospholipid- and Ca2+-binding protein, which has been identified as one of the Gal-3-interacting proteins. Gal-3 might also function by interacting with intracellular apoptosis regulators such as B-cell lymphoma 2 (BCL2), or might facilitate the localization of BCL2 to the mitochondria, although definitive evidence for such a function is lacking. The effect of Gal-3 in the regulation of apoptosis depends on its subcellular localization: cytoplasmic Gal-3 is anti-apoptotic, whereas nuclear Gal-3 is pro-apoptotic.

Galectins and tumour metastasis

The progression from primary to metastatic tumours is a multigenic and multistep process that involves cell–cell and cell–extracellular matrix (ECM) adhesion, cell invasion and/or migration and angiogenesis. Different galectins seem to have key roles at different steps of the processes. Some members function together with integrins to mediate tumour cell adhesion, including adhesion to ECM proteins and homotypic cell adhesion, but can also inhibit adhesion, which could result in tumour cell detachment. The overall effect can be either the promotion or the inhibition of metastasis. Galectin-1 (Gal-1), Gal-3, and Gal-8 can influence tumour cell migration and invasion by engaging integrins (also involved in cell survival and angiogenesis) or other cell-surface proteins involved in cell migration. Gal-3 can also affect the intrinsic motility of cells by remodelling cytoskeletal elements associated with cell spreading — microfilaments — through as yet unidentified mechanisms. Gal-3 can promote angiogenesis by promoting endothelial cell migration.

Galectins dan imune terkait tumor dan respon inflamasi

Galectins (digambarkan di sini sebagai Gal-1–Gal-9) diekspresikan oleh sejunlah sel sistem imun yang berbeda dan sel inflamatori dan mengatur fungsi dari sel-sel tersebut, thereby affecting the immune and inflammatory responses developed by the host against tumours. In addition, galectins released by the tumours can modulate various inflammatory responses. As shown in this diagram, galectins can behave as pro-inflammatory or anti-inflammatory mediators by modulating the physiology and responses of immune cells, including macrophages, T and B cells, neutrophils, eosinophils and mast cells. There is increasing evidence that some tumour-associated inflammatory responses have a positive impact on tumour progression and survival, whereas others can inhibit tumour growth and kill cancer cells. By positively or negatively (indicated by upwards and downwards arrows) affecting the inflammatory response surrounding the tumours, galectins indirectly influence tumour progression and metastasis. ECM, extracellular matrix; IL2, interleukin 2; IL5, interleukin 5; IFN, interferon; NADPH, nicotinamide adenine dinucleotide phosphate, reduced form; TCR, T-cell receptor.

Anti-tumour immune responses and galectin-mediated escape mechanisms

Immune responses can be categorized into two general types: cellular (involving CD8+ and CD4+ T-helper (Th) cell type 1 cells) and humoral (involving CD4+ Th2 and B cells) immune responses, which may impact tumour growth in several ways. Tumour-specific CD8+ T cells (T CD8+) are activated by the release of interleukin 12 (IL12) by antigen presenting dendritic cells, which express B7 and CD40 (co-stimulatory molecules required for T-cell activation). These activated CD8+ T cells can kill tumour cells directly. One subset of CD4+ T cells (Th1 CD4+), promotes the activation of CD8+ T cells through their secreted interferon (IFN). The other CD4+ T cell subset, (Th2 CD4+) stimulates an antibody-mediated immune response and activates B cells by releasing IL4. Th2 cells suppress Th1 responses and activate eosinophils by releasing IL5. CD8+ and CD4+ T cells secrete IFN, a Th1 cytokine, which can sensitize tumour cells to CD8+ T cells and activate other immune cells, thereby favoring tumour destruction. T cells use two main mechanisms to kill tumour cells: the death receptor pathway and the granule exocytosis pathway, which involves the secretion of perforin and granzymes. Tumours can evade immune responses by secreting immunosuppressive cytokines and soluble inhibitory factors, including galectin-1 (Gal-1). Gal-1 contributes to immune evasion by inducing apoptosis in effector T cells. Other galectins, including Gal-2, Gal-3 and Gal-9, also induce T-cell apoptosis, although their contributions to tumour-immune escape in vivo have not yet been demonstrated.

Referensi

Liu FT and Rabinovich, GA, 2005, Galectins as modulators of tumour progression, Nature Review Cancer, 5, 29-41

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One thought on “Galectins Sebagai Modulator Progresi Tumor

  1. mhn ijin untuk copy buat referensi, Thanks.

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