Galectins and Pathologies: Role of Galectin-3 in the Communication

Chapter 14

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Galectins and Pathologies: Role of Galectin-3 in the Communication between Leukemia Cells and the Microenvironment Nora Heisterkamp,*,1 Fei Fei,1 and John Groffen2 1Section

of Molecular Carcinogenesis, Division of Hematology/Oncology and The Saban Research Institute of Children’s Hospital, 4650 Sunset Boulevard, Los Angeles, California 90027, USA 2Departments of Pediatrics and Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA *E-mail: [email protected]

Our recent studies in a tissue co-culture model have shown that Galectin-3 is synthesized by both protective stromal cells and by precursor B-lineage acute lymphoblastic leukemia cells. Galectin-3 binds to the surface of these leukemia cells. Also, these studies, and those of others in chronic myeloid leukemia cell lines, show that drug treatment further increases expression of endogenous Galectin-3, and that elevated Galectin-3 levels protect leukemia cells. For therapeutic purposes, therefore, blocking Galectin-3 binding or reduction of Galectin-3 levels is an important goal. This may require the development of inhibitors with (1) a long half-life, (2) high specificity for Galectin-3 and (3) high affinity for its carbohydrate recognition domain. Alternative approaches include designing Galectin-3 inhibitors that are targeted to specific cell types, or the identification and targeting of the cell surface glycoproteins that regulate Galectin-3 biological effects. This mini-review describes literature data on interactions of extracellular Galectin-3 with glycoproteins on the cell surface and their possible connection to leukemia as well as the intracellular activity of Galectin-3, its possible regulation by interactions with glycoproteins, and its effect on leukemia cell resistance against therapeutic drugs. In vitro and in vivo

© 2012 American Chemical Society In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


experiments using Galectin blockers of a polysaccharide nature (GM-CT-01 and GR-MD-02) are also reviewed. Based on these data, it is reasonable to assume that interference with the carbohydrate-binding activity of Galectin-3 in a wide range of leukemias may be beneficial (1) as first-line treatment, in combination with other drugs, to enhance anti-leukemia activities (2) as a possible marker and contributor to the persistence of leukemia cells in protective niches, and the presence of minimal residual disease in the bone marrow (3) as a method to modulate supportive cells in the microenvironment of the leukemia cells, including bone marrow stromal cells.

Introduction For successful utilization of a biomolecule as drug target in leukemia, the relative importance of that molecule to leukemia cell survival, compared to its functional significance for normal cells is a key consideration. In that respect, Galectin-3 is an interesting but complex target with multiple domains, locations and possibly functions. Galectin-3 is expressed in a number of different leukemias, but immune cells and stromal cells, which may profoundly alter the way leukemia cells respond to drugs, can also express Galectin-3. Thus, inhibition of Galectin-3 may have anti-leukemia effects through mechanisms other than direct effects on the leukemia cells.

Interactions of Extracellular Galectin-3 Galectin-3 is found both extracellularly and intracellularly. It was originally discovered as Mac-2, a cell surface marker on macrophages. Human Galectin-3 is a relatively small protein (30-35 kDa) that can be subdivided into N-terminal, R (-Pro-Gly-Tyr-Repeat) and Carbohydrate Recognition (CRD) domains of around 20, 100 and 130 aminoacids (1). High-affinity carbohydrate ligands identified for Galectin-3 include tri-and tetra antennary N-linked glycans that are N-acetyllactosamine modified on cell surface proteins. Galectin-3 only recognizes glycans containing a polyLacNAc extension (2–4) and sialylation of these glycans inhibits Galectin-3 binding (5–7). Interestingly, Galectin-3 is unique among galectins in that it can form pentamers through its N-terminal domain, which is located outside of the CRD. These Galectin-3 pentamers have the ability to interact with multivalent cell-surface glycoproteins and through this mechanism promote lattice formation and receptor clustering, crosstalk between cell surface carbohydrate-modified integrins and signaling receptors; and promote or prevent endocytosis of such molecules. Thus, extracellular Galectin-3 is thought to mainly affect cell function through its carbohydrate-binding activity and interaction with cell surface proteins, forming lattices that can, for example, enhance residency at the cell surface. However, the precise biological outcome of this interaction differs, depending on the cell type and on the proteins with which it forms a lattice (5, 8). For example, 250 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

Galectin-3 binding to the TGFβRII delays its constitutive endocytosis in murine mammary epithelial tumor cell lines, resulting in attenuation of TGFβ-generated signals (9). Interactions with the transferrin receptor CD71, the β1 integrin CD29 and the tyrosine phosphatase CD45 on T-cells promotes apoptosis (10), whereas interactions with CD98 (slc3a2) promotes macrophage M2 polarization (11). Thus, the signal generated by extracellular Galectin-3 depends on the presence and modification of glycoproteins it interacts with on the cell surface.


Leukemia Drug Resistance Leukemia cells are protected against many drugs through interactions with their microenvironment, which consists of both the extracellular matrix and cellular components. Protective effects of stromal cells to leukemia cells when these are treated with drugs have been documented extensively by us in pre-B acute lymphoblastic leukemia (ALL) (12–14) and have also been reported in chronic myeloid leukemia (CML) (15), acute myeloid leukemia (AML) (16), and in chronic lymphocytic leukemia (CLL) (17–20). The resistance to drug treatment that this type of protection provides is named environmental-mediated drug resistance (EMDR) (21–23). Meads et al (24) argued that EMDR is likely to be a major source of relapse. Leukemia cells make contact with the microenvironment through cell surface structures of which the protein components have been the easiest to approach experimentally and have therefore been the most well-studied. However, all cells are covered by a dense network of glycolipids, glycoproteins, glycophospholipid anchors and proteoglycans. The importance of these structures is illustrated by the fact that more than 1% of the genome is involved in generating the developmentally regulated and tissue-specific glycosylation characteristics of each cell type (25).

Extracellular Galectin-3 and Leukemia This dense layer of carbohydrates constitutes the “face” of the cell that is presented towards the outside world and is the contact interface between leukemia cells and the cells in the microenvironment that protect them. Extracellular Galectin-3 is an important component of the microenvironment of non-transformed cells, mediating cell migration, cell adhesion, and cell-cell interactions through its carbohydrate-binding properties. Our data show that human or mouse pre-B ALL cells communicate with protective stromal cells in a tissue culture setting. These stromal cells secrete Galectin-3, which binds to structures on the surface of the ALL cells. The Galectin-3 is internalized and this appears to generate a signal in the ALL cells for the transcription, synthesis and cell surface expression of Galectin-3. Moreover, the treatment of the ALL cells with conventional (vincristine) or targeted (nilotinib) drug therapy at doses that allows EMDR results in enhanced Galectin-3 production (Fei et al., manuscript in preparation). 251 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


Induction of Galectin-3 in leukemia through contact with the microenvironment does not seem to be restricted to pre-B ALL. Recently, Yamamoto-Sugitani et al reported that the co-culture of the CML cell line MYL with the stromal cell line MS5, or adhesion to fibronectin, also significantly induced the synthesis of Galectin-3 mRNA. Upon co-culture with MS5 stromal cells, increased Galectin-3 protein was detected in three different CML cell lines, in the T-cell leukemia cell line Jurkat, and in the myeloid leukemia cell line HL60 (26). In leukemias, different effects of extracellular stimulation through the addition of Galectin-3 have been reported. For example, extracellular supplementation with Galectin-3 did not affect the sensitivity of K562 or MYL cells to imatinib or doxorubicin (26). In contrast, Suziki and Abe reported that Galectin-3 induced cell death of the diffuse large B-cell lymphoma cell line HBL-2 (27).

Intracellular Galectin-3 In general, intracellular Galectin-3 is regarded as anti-apoptotic as shown in, among others, in the CML cell line K562 treated with cisplatin or LY294002 (26, 28, 29). Treatment of K652 with different drugs in the absence of stroma also induced increased Galectin-3 expression, and surviving cells contained elevated Galectin-3 compared to the original cells. Overexpression of Galectin-3 in K562 or knockdown of Galectin-3 levels increased or decreased sensitivity to apoptotic agents (28). Similar studies and results were reported in the CML cell line MYL (26). In some cell types, Galectin-3 was shown to inhibit ROS production and prevent alteration of the mitochondrial membrane potential (26, 28–32). The Galectin-3 CRD contains a Bcl2-homology domain (BH1) with the conserved N180-W181-G182-R183 motif that mediates complex formation with Bcl2 and protects cells from apoptosis. The same domain also mediates Galectin-3-Galectin-3 homodimer formation and Galectin-3/Galectin-3 and Galectin-3/Bcl2 interactions are specifically inhibitable by 25 mM lactose but not sucrose (33). Thus, the interesting possibility exists that some of the intracellular activities of Galectin-3 are also regulated by interactions of the CDR with glycoproteins or other carbohydrate-bearing macromolecules.

Which Galectin-3 Function Should Be Aimed at in Practical Therapy? As briefly reviewed above, Galectin-3 has at least two locations and possibly distinct functions that are relevant in the context of leukemia cell survival: a direct anti-apoptotic effect inside the cell, which may be independent of glycan binding, and a possibly indirect extracellular effect in modulating signal transduction strength through carbohydrate-binding-dependent interactions. Those therapeutics that interfere with the extracellular activities of Galectin-3 appear to be easier to target, and, based on our results in pre-B ALL, may be most 252 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

relevant to the problem of environmental-mediated drug resistance and minimal residual disease.

How To Use Galectin-3 as Drug Target?


Exposure of some cell types to extracellular Galectin-3 may cause apoptosis, but available data for pre-B ALL and CML suggest that attenuation of the extracellular effects of the Galectin-3 in the microenvironment may have clinical benefit. As mentioned above, there are several theoretical ways to accomplish this: a.

b.

c.

d.

Approaches to prevent expression or activation of defined, critical poly N-acetyllactosamine-modified cell surface glycoproteins with which Galectin-3 interacts. In pre-B ALL cells this could include CD45, CD43, integrin β1 or CD71, all of which are expressed on pre-B ALL cells. Although this approach would allow a fine-tuning of the effects of inhibition, it would require the precise identification of such glycoproteins and the intracellular effects of Galectin-3 engagement. Approaches to increase sialylation of poly N-acetyllactosaminemodified cell surface glycoproteins with which Galectin-3 interacts, through inhibition of extracellular sialidases, or the stimulation of sialyltransferases. Sialydation is known to have a marked effect on the ability of Galectin-3 to interact with cell surface glycoproteins [reviewed in (6)]. However, currently, the targets for Galectin-3 binding that confer a survival benefit to leukemia cells and can be blocked by their sialylation are not known, nor have the sialyltransferases or sialidases that would regulate this modification been precisely defined in leukemia cells. That modulation of the sialylation can affect Galectin-3-mediated functions is illustrated by the report of Suzuki and Abe, who increased the pro-apoptotic effect of exogenously added Galectin-3 on the diffuse large B-cell lymphoma cell line HBL-2 by pre-treatment with Vibrio Cholerae neuraminidase (27). Approaches to inhibit intracellular Galectin-3 protein production or prevent extracellular secretion of the protein. The detailed knowledge needed to manipulate these processes is not available. Approaches to block the interaction of the CRD of Galectin-3 with accessible polyLacNAC-extended glycans. This is the only approach for which data are available.

To the best of our knowledge, the exact mechanism of action of such glycanbased Galectin-3 inhibitors, or their fate in either a tissue culture setting or in animals has not been documented. Those that bind to the CRD of Galectin-3 would be expected to sequester extracellular Galectin-3 produced by protective stromal cells as well as by the leukemia cells, perhaps followed by enzymatic degradation in the extracellular space. Alternatively, since Galectin-3 is able to form multimers, it is possible that some of the Galectin-3 molecules bind the 253 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.

inhibitor, others bind to their natural ligands on the cell surface, and that this as a whole is internalized as a large macromolecular complex. Finally, if glycan-based inhibitors are internalized in a Galectin-3 independent manner, they could form complexes with intracellular Galectin-3 and through this mechanisms block the anti-apoptotic activity of Galectin-3 in leukemia cells when these are treated with therapeutic drugs.


Evidence for Therapeutic Effect of Blocking the Interaction of the CRD of Galectin-3 with Accessible Polylacnac-Extended Glycans a. In vitro Exposure of pre-B ALL cells to chemotherapy (vincristine) or to targeted drugs (nilotinib) in the presence of GM-CT-01 (also known as Davanat) and GR-MD-02 (another polysaccharide), enhances the effect of the drugs on cell proliferation and viability (Fei et al,, manuscript in preparation). Yamamoto-Sugitani et al (26) reported that fractionated citrus pectin powder as a Galectin-3 inhibitor caused cell death in MYL cells, in MYL cells overexpressing Galectin-3, and in MYL cells treated with imatinib in the presence of MS5 stromal cells in tissue culture. The modified citrus pectin GCS-100 has been described as an inhibitor of Galectin-3 and was used to treat multiple myeloma cell lines and primary patient samples in the context of drug resistance (34, 35). b. In vivo Few animal studies using anti-Galectin-3 reagents against hematological malignancies have been published. Demotte et al (36) used GCS-100 to activate tumor-infiltrating T-cells in a mouse transplant model of mastocytoma. The C-terminal end of Galectin-3 showed anti-cancer activity alone and combined with bortezomib in NOD/SCID mice transplanted with a human multiple myeloma cell line (37). Interestingly, these authors mentioned that “the primary activity of Gal-3C in vivo may be mediated by interactions involving the tumor microenvironment rather than by direct cytotoxicity to the multiple myeloma cells…”

Opportunities and Challenges Based on the data described above, it is reasonable to assume that interference with the carbohydrate-binding activity of Galectin-3 in a wide range of leukemias may be beneficial 1) as first-line treatment in combination with other drugs, to enhance anti-leukemia activities 2) as a possible marker and contributor to the persistence of leukemia cells in protective niches, and the presence of minimal residual disease in the bone marrow 3) as a method to modulate supportive cells in the microenvironment of the leukemia cells including bone marrow fibroblasts. 254 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


A formidable challenge is to effectively ablate Galectin-3 activity and/or levels. As described in our in vitro studies, Galectin-3 is made by both protective stromal cells and by pre-B ALL cells. Moreover, our data indicate it is secreted by the stromal cells, and binds to the surface of pre-B ALL cells (Fei et al., manuscript in preparation). Finally, these studies, and those in the CML cell lines, show that drug treatment increases endogenous levels of Galectin-3 even further. The challenge will thus be to sufficiently block or diminish Galectin-3 as to achieve a biological effect in vivo. This may require the development of inhibitors with 1) a long half-life, 2) high specificity for Galectin-3 and 3) high affinity for its CRD. Alternative approaches could be to design Galectin-3 inhibitors that are targeted to specific cell types, or the identification of the cell surface glycoproteins that regulate Galectin-3 biological effects.

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Galectins and Pathologies: Role of Galectin-3 in the Communication

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