Jurnal Internasional Galektins ekstraseluler sebagai pengendali sitokin pada kanker hematologi
Extracellular Galektins as controlling cytokines in hematologic cancer
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Galectin and cytokines are secreted proteins whose rate is a prognostic factor for some cancers Extracellular Galektins bind to glycoproteins that decorate glycans and are produced excessively in most cancers. accumulative studies suggest that galectin regulates cytokines during the development of cancer.Although galectin alters the function of cytokines by binding to glikans to decorate cytokines or their receptors, cytokines can also regulate the expression and function of the galactin.This review revised this complex interaction and its clinical implications, particularly in haematological cancers
Galektin is a family of 17 proteins that have a dominant n the same carbohydrate binder. They are ubiquitous proteins found in the nucleus, cytoplasm, and extracellular space. Intracellular gallectin may form protein-protein interactions, whereas extracellular galectin interacts primarily with glikans that decorate glycoproteins. 1 2 The main source of extracellular galectins in cancer are myeloid cells and tumors, but other cells such as mesenchymal cells and lymphoid cells can also excrete the galectin. 3 ⇓ ⇓ - 6 All the galectin is multivalent because of oligomerization or some carbohydrates that bind the domain per protein. 7 Galectin binds glycans loosely and very cooperatively: they recognize some glycan patterns and form galectin-glycan lattices whose binding forces are correlated with the number of defined interactions. Galectin is involved in various processes in both homeostasis and disease. Some of the gallectin is produced excessively in human malignancies and autoimmune diseases. 3 4 High expression of gallectin is often an independent prognostic factor that is unfavorable for the development of diseases of different cancers (see Table 1 for a complete list of hematologic malignancies). 8
Cytokines are intercellular signals secreted by different cell types as small soluble proteins. They regulate the fate of the cell, especially the fate of immune cells, by interacting with specific receptors on the surface of the target cell and then triggering different cell programs. Many cytokines, like most proteins that are secreted, are posttranslationally decorated with glycans. Glycosylated cytokines are known to determine the biological activity and cytokine stability. 9
Although the galectin and cytokines appear to be controlled on a reciprocal basis, more is known about how the gallectin affects cytokines. 10 The currently available data on this subject represent most observations and correlations, with only a few articles digging deeper into the regulatory mechanism. In addition, results are often biased by the scientific focus of the author on a particular galectin. Thus, we can not exclude that another galectin may have the same or opposite effect on the regulation of cytokine on the observed galectin. In addition, many also neglect to investigate the role of intracellular extracellular galaxies in cytokine regulation. In this article, we discuss some of the interactions of gallectin-cytokines that have important consequences in the development of most hematological and some non-protective cancers (a comprehensive list is indicated in Table 2 ). Of particular interest are the emerging ways in which extracellular galectins regulate cytokines by affecting their expression and secretion rates, by inhibiting cytokine diffusion through extracellular matrix, and / or by modulating cytokine signaling via appropriate receptors ( Fig. 1 ). We integrate available data for the galectin, propose several hypotheses, and ask important questions in the field."data-icon-position =" "data-hide- Figure 1. " src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://www.bloodjournal.org/content/bloodjournal/132/5/484/F2.medium.gif" width="305" height="440"/> 
Galectin regulates expression and secretion of cytokines
Galectin-1 induces immune tolerance through cytokine regulation, decreased T helper 1 (Th1) and elevated Th2 cytokine levels 11 12 Galectin-1 protective role in some models autoimmune mouse seems related to modulation i ni. balance of cytokines, in which the preferred interleukin-5 (IL-5) and IL-10 secretion and interferon-γ (IFN-γ), IL-2, IL-12, IL-17, and tumor necrosis factor-α (TNF- α) secretion is inhibited. 11 13 ⇓ - 15 This effect may be related to the galectin-1 that causes apoptosis Th1 and Th17. subset of lymphocytes. 16 In human malignancies, high expression of protein galectin-1 correlates with disease progression, aggressiveness s, and poor survival in chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). 17 18 In both cases, galectin-1 is secreted by a stromal tumor and supports the tumor. growth and survival. Specifically, in CLL, the stroma of galectin-1-secreting is represented by nursing-like cells (NCL), a monocytic differentiated cell type. 19 NCLs are known for protecting leukemia clones from spontaneous and drug-induced apoptosis. 19 Tapping galectin-1 in NCL reduces their expression of the B-activating factor and secretion of IL-10 and CCL3 by cultured CLL B cells. 17 Importantly, high serum levels of IL-10 and CCL3 correlated with a shorter time for the first treatment and survival of CLL patients 20 Although not evaluated by this author, the interaction of B- activation with CD86 is known to induce IL-10 secretion by B cells. 21 These NCL-CLL contacts may represent the mechanisms underlying IL-10 regulation. Furthermore, the secreted galectin-1-NCL activates the survival signal through the B-cell receptor in CLL cells. 17 Galectin-1 is also a pre-B-cell receptor ligand that induces receptor groupings, representing the first checkpoint of cell differentiation B and can further support the survival of CLL 22 In MM, galectin-1 expression is directly induced by the bone marrow hypoxia microenvironment. 18 Galectin-1, by unexplored mechanisms, increases the proangiogenic expression of CCL2 and MMP9 and reduces angiostatic expression of SEMA3A and CXCL10. 18 As a result, injecting mice with myeloma cell lines where galectin-1 was torn down reduces tumor blood vessel density, and most probably due to this anti-angiogenic effect, as well as tumor growth and tumor burden. 18 Interestingly, galectin-1 and -3 have important proangiogenic effects independently of cytokine regulation, especially by binding of dir ectly to vascular endothelial growth factor receptors 23 In short, galectin-1 and Another galectin released by tumor stroma helps the tumor by increasing the expression of protumoral cytokines, chemokines, and angiogenic factors. However, the exact mechanism is still unknown. 24
Galectin-3 is considered proinflammatory and prometastatic. 3 4 The proinflammatory effects of galectin-3 are only reported on non-ecologic tumors and consist mostly of galactic-cytokine correlations. In pancreatic ductal adenocarcinoma, galectin-3 expression is higher than normal pancreatic tissue and correlates with higher IL-8, CCL2, and CXCL1 expression. 25 Increased galectin-3 is also reported in serum colon cancer patients where it correlates with higher granulocyte colony-stimulating factor (G-CSF), IL-6, and sICAM-1 levels. 26 27 Galectin-3 related cytokines are considered prometastatic because they increase drug resistance and adhesion and line cell cancer migration to and through the endothelium. 26 28 29 Galectin-3 catalyzes the expression of cytokines through the promotion of the Ras / MEK pathway, leading to increased AKT survival signals and the production of NF-κB cytokines. 27 30 31 Although most studies show that extracellular-3 galectin promotes this signal path, my proper chanism of action is still unknown. Galectin-3 has been proposed for crosslinked glycoprotein receptors on the cell surface, but both agonistic and antagonistic effects on downstream signals from receptors have been reported (eg, Markowska et al 19659095 32) 19659097 vs. Petit et al 33 ). Galectin-3 is an important prognostic factor for the development of severe disease in some leukemia (see Table 2 ) and has been correlated with bone marrow induced bone-induced resistance in CLL and AML in vitro. 34 35 In short, although galectin-3 is clearly involved in the development of proinflammatory and prometastasis of cancer, its exact role and mechanism of action is still elusive.
Galectin-4 secreted by intestinal epithelium healthy and human colorectal cancer cell lines and bind to the surface of T cell lamina propria mucosa and colorectal cancer cells. 36 37 Line of colorectal cancer cells treated in vitro with a neutralizing antibody of galectin-4 proliferate more and secrete CCL2, CCL5, CSF-2, and ICAM-1 dissolved by an unknown mechanism. 37 Other authors confirm the antitumoral effect of galectin-4 by knocking down galectin-4 in preclinical tumor models. 38 Interestingly, this author observes that silencing galectin-4 is associated with higher IL-6 expression. Furthermore, galectin-4 is associated with CD3, inhibiting T cell activation and proliferation in CD3 / CD28 stimulation and reducing downstream secretion of IL-6, IL-8, IL-10, and TNF-α. 36 However, it is unclear whether the binding galectin-4 CD3 is the root cause of downstream T cell dysfunction.
Galectin-9 the study yielded conflicting results. Galectin-9 protein levels increased in AML cells and in blood plasma of AML patients 39 40 The development of AML is associated with fatigue and T-cell dysfunction, including reduced cytokine secretion 40 41 T-cell fatigue in AML has been associated with a galectin-9 interaction with Team-3, a regulated inhibitory receptor on the surface of active and exhausted T cells.  40 Treating mouse AML models with human-IgG Human-3 IgG fusion proteins and anti-PD-L1 antibodies reduces tumor burden and improves rat survival rates. In addition, 9-galvanic KO rat is more resistant to AML. 40 However, other authors have recently described another partner of Team-3, called CEACAM-1, which governs the expression of Team-3 and its T cells. fatigue trigger function. 42 Therefore, therapeutic effects inhibiting Team-3 may not be related to galectin-9. It should be noted that CEACAM-1 and Team-3 are both N-glycosylated, and thus, galectin-9 may bind both proteins, and stabilize or block their associations, which have not been studied. A troubling factor is that Team-3 exists on the cell-bound and soluble surfaces, following proteolytic shedding. 39 Only some writers consider this. 39
The Tim-3 effect on NK cell tumoricidal function is also inconsistent. Addition of galectin-9 to Team-3-positive NK cells weaken NK kill human AML cell line in vitro. 39 Conversely, galectin-9 is shown to decrease the activity of killing of human NK cells by a Team-3-independent mechanism. 43 The report on the effect of galectin-9 on IFN-are production is also contradictory. 42 43 Galektin modulates cytokine signaling
Binding galektin to glycosylation receptors modulates how cytokines engage with receptors and subsequent signaling pathways. For example, GCS-100 polysaccharide-3 polysaccharide polysaccharides has been shown to inhibit responses to TNF-α, IGF-1, and IL-6 cytokines by myeloma cell lines by unidentified mechanisms. 44  GCS-100 also reduces myeloma proliferation by promoting tumor cell apoptosis. 44
Blouin and his colleagues elegantly point out that mutations in IFNγR2, leading to the addition of new N-glycosylation sites, lead to the complete elimination of IFN-γ signaling. 45 This glycosylation strengthens the galectin-3 association with IFNγR2, which in turn limits IFNγR2 into the nanodomain actin membrane from which it can not signal. 45 -glycosidase, galectin antagonist, or knock down the expression of galectin-3 saves the distribution of IFNγR2 to the lipid nanodomain on the plasma membrane and consequently restores signaling transduction.45
Extracellular Galektins retain cytokine diffusion
We recently reported that the gallectin modulates the function of cytokines through a novel mechanism: galectin binds glycosylated cytokines directly and consequently restrain it in an extracellular matrix. Specifically, galectin-3 binds glycans to IFN-γ and IL-12, reducing their diffusion through the collagen matrix. 46 Ex vivo treatment of human tumor biopsies with galectin antagonists and IFN-γ increases the production of CXCL9 in most samples compared with treatment with IFN-γ alone. Moreover, only in highly infiltrated samples (heat tumors), the galectin inhibitor is able to induce the production of CXCL9, even when IFN-γ is not exogenously added. Since we have previously shown that galectin antagonists do not induce CXCL9 per se, galectin-3 inhibition of heat tumors should release IFN-γ endogenous pretrapped. 46 Additionally, the galectin-3 antagonist improves IFN- γ-induced CXCL9 / 10/11 production by tumors in humanized melanoma mouse models. The resulting chemokrin chemokrin increases infiltration by specific antitumor CD8 T cells and delayed tumor growth.  46
Cytokines regulate the expression and function of galectin
Little is known about how cytokines regulate the expression of the galectin. TNF-α and IFN-γ induce galectin-9 secretion by mesenchymal stem cells (MSC) in vitro. 47 In fact, the authors hypothesize that the secretory gecko-9 is responsible for suppressing MSCs against lymphocyte activation. 47 Other authors have confirmed that the galectin-9 expression is regulated by IFN-γ and IL-10 and regulated by IL-1. 48 49 
Smith and colleagues have recently reported an interesting example of a cytokine that affects the function of the galektin in the nontumoral mouse model. The authors point out that during a chronic viral infection, where sustained induction of IL-10 occurs, IL-10 increases the expression of the 5-mg, Golgi-resident glycosyltransferase. 50 Mgat-5 catalyzes the production of high-branched N-glycoprotein which is a high affinity bond site for the galectin. Consequently, the sustained existence of IL-10 during chronic viral infection enhances the galectin-3 that binds the surface of CD8 T cells and decreases the function of T cells. 50 Galectin-3 binding glycosylated receptors in human T cells has been associated with increased the threshold of T-cell receptor activation and CD8 dysfunction 33 50 ⇓ - 52 This dysfunction is directly related to the inability by CD8 to secrete IFN-γ, TNF-α , and IL-2. 33 Thus, an interesting cross-talk of interesting cytokines seems to work, in which the continued existence of IL-10 increases the galectin -3 ligand expression, and therefore, binds to galectin-3. This in turn blocks the secretion of Th1 cytokines.
In addition, IL-4 and IL-6 have been described to regulate the expression of some glycosyltransferases and consequently alter protein glycosylation. 53 However, the authors did not analyze the specific consequences of glycosylated changes in the function of galectin.
Conclusions and future directions
Galectin and cytokines seem to be regulated mutually during homeostasis and disease, but most evidence which are readily available indirectly and comprise a corresponding level of protein expression. Further research is needed to reveal the direct relationship between these 2 families of proteins. Scientists are challenged in their search for a specific and direct role, since the binding of the galektin makes them pleiotropic and able to modulate the function of cytokines at various levels ( Figure 1 ). How is functional redundant galectin for cytokine regulation?
The main mechanism of action for extracellular galektins is binding and binding cross-linking glycosylation proteins, such as receptors, matrix proteins, and cytokines themselves. 54 Hence, the status of cell glycosylation affects how the galectin binds to its surface. 16 This status is linked to the cell's metabolism and genetic program and can be altered by cytokines, which can thus directly modulate the expression of the galectin and indirectly alter the galectin binding. and function by controlling the cell glycosylation status. 50 53 Is glycosylation change a new way to evaluate the effects of therapeutic cytokines? Most cancer cells are known to have deviant glycosylated status. Whether galactin appears to be involved in tumor drug resistance (see Table 2 ), the combination of a current galactin inhibitor with current cytotoxic drugs may increase the efficiency . current treatments. We believe that galectin can be an attractive therapeutic target for three main reasons: they are overproduced as cancer develops, their presence correlates with a poor prognosis, and they seem to regulate the production and function of cytokines.
The authors say thanks to Thibault Hirsch for the revised manuscript.
This review follows work supported by the 2010-175 grant from Fondation Contre le Cancer (Belgium) and grants 3,4514.12 from Fonds de la Recherche Scientifique Médicale-FRSM (Belgium).  Essay  Contribute: MG-A. and P.v.d.B. designing manuscripts; M.G.-A. writing manuscripts; A.M.B. edit the manuscript, create the numbers, and greatly contribute to the writing.
Disclosure of conflicts of interest: The authors declare no competing financial interests.
Correspondence: Monica Gordon-Alonso, Institut de Duve, Université Catholique de Louvain, Avenue Hippocrate 74, Bte B1.74.03, B-1200 Brussels, Belgium; e-mail:; and Pierre van der Bruggen, Institut de Duve, Université Catholique de Louvain, Avenue Hippocrate 74, Bte B1.74.03, B-1200 Brussels, Belgium; e-mail: .
- Submitted 25 April 2018.
- Received May 31, 2018.
- © 2018 by the American Society