Galectins as Novel Targets for the Treatment of Malignant Gliomas

Chapter 10

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Galectins as Novel Targets for the Treatment of Malignant Gliomas Herwig M. Strik*,1 and Matthias Ocker2 1Department

of Neurology and Medical School, University of Marburg, Baldingerstrasse, D-35043 Marburg, Germany 2Institute for Surgical Research, Medical School, University of Marburg, Baldingerstrasse, D-35043 Marburg, Germany *E-mail: [email protected]

The treatment of brain tumors is associated with important limitations, not only because complete surgical resection is impossible, but also because blood-brain barrier protects the brain from external substances and is permeable only for small-molecular, lipophilic substances. The most common malignant brain tumors, glioblastomas, are associated with a grim prognosis of approximately 12 months in unselected series. In addition to special aspects associated with their intracranial localization, gliomas have a marked resistance against antiapoptotic stimuli. A high migratory potential, intense neoangiogenesis and a strong immunosuppressive environment also contribute to the usually rapid proliferation in spite of all therapeutic efforts. An ideal anti-glioma compound should be orally available, small-molecular and lipophilic and modulate several or all of the known factors proliferation, apoptosis resistance, angiogenesis and immune escape. Among other molecular factors, carbohydrate-binding galectins -1, -3, -4 and -8 – are known to be expressed in malignant gliomas. Galectin -1 and -3 have been shown to be associated with proliferation, apoptosis-resistance and migration. Effects on angiogenesis and immune escape may also exist. Intra- or extracellular modulation of galectin functions therefore appears to be a promising strategy for the treatment of malignant gliomas.

© 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.


Introduction The most common malignant brain tumor, glioblastoma multiforme, is also the most aggressively growing, classified as grade IV by WHO. The median survival in unselected series still does not exceed approx. 12 months (1) and 14-17 months in large chemotherapy trials (2, 3). Neither operation nor ionizing irradiation or systemic antineoplastic treatment are able to cure patients suffering from this disease. Several biological features are known to contribute to the poor response to antineoplastic treatment and aggressive growth of these tumors. One prominent characteristic of gliomas is a marked resistance against apoptosis-inducing stimuli (4). Mutations of p53, for example, are found in numerous glioblastomas and cause a deficiency in cell death (5). The balance between pro- and antiapoptotic factors, called the apoptotic rheostat, is shifted towards antiapoptotic functions such as upregulation of anti-apoptotic and downregulation of pro-apoptotic members of the B-cell lymphoma 2 (BCL-2) protein family (6). A comparison of individual tumors even showed an additional anti-apoptotic shift during the development from primary to recurrent disease. Such mechanisms may contribute to the resistance against radiotherapy or chemotherapy and lead to even increased protection during the course of the disease. Conventional tumor therapy like chemotherapy or ionizing irradiation aims at inducing apoptosis. Therefore, suppression of antiapoptotic stimuli may enhance the effect of such treatments (7). Alkylating agents are most often applied to treat malignant gliomas. ACNU (nimustine), BCNU (carmustine) or CCNU (lomustine) efficiently pass through the blood-brain barrier and have been effective in numerous studies. The combination of ACNU with cytarabinoside (Ara-C) or etoposide (VM26) achieved a median overall survival of approx. 17 months, which is still among the best results in large multicenter trials (2). The hematotoxicity observed with these combinations, however, was considerable. Another alkylating agent, temozolomide, is an orally available imidazotetrazine derivative with good penetration through the blood-brain barrier and favorable toxicity profile. In a large multicenter trial, addition of temozolomide was significantly more effective than radiotherapy alone (3). Ever since this study was published, efforts have been made to further enhance the effect of this chemotherapeutic agent. Dose-dense application of temozolomide aims at depleting MGMT, an important anti-alkylating molecule that is able to revert the effect of temozolomide (8). The effect of this strategy, however, is limited and more efficient inhibition of apoptosis-resistance desired. Another important feature of malignant gliomas is a marked potential for migration and invasion (9). Since glioma cells can migrate up to several centimeters from the main tumor localization (10), local treatment strategies like surgery or radiotherapy are not able to cure patients. Systemic chemotherapy will probably be less effective in the infiltration zone surrounding the tumor because the blood-brain barrier is intact in this region, as opposed to the main tumor bulk, and migrating cell have a reduced proliferation rate, so a reduced response to radiation and chemotherapy has to be expected (11). Inhibition of 172 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


migration and invasion of glioma cells might therefore enhance the effect of local tumor treatment. For example, matrix metalloproteinases like MMP-2 and -9 and integrins like αvβ3 have been shown to markedly influence glioma cell migration (12) and might therefore be suitable targets for future therapeutic intervention. One crucial feature of cells to form a well-functioning tumor tissue is to gain sufficient blood supply. An important role for glioma angiogenesis has been proven for hypoxia-inducible factor-1α (HIF-1α), transforming growth factor beta (TGF-β), basic fibroblast growth factor (bFGF) and – most importantly – vascular endothelial growth factor (VEGF) (13). Conversely, anti-angiogenic endostatin is downregulated during the malignant transformation of human gliomas (14). After first discouraging results, numerous studies have shown promising results with the anti-VEGF antibody bevacizumab (15), proving the importance of this strategy. A further prominent feature of malignant gliomas is the abundant infiltration with up to 30% of monocytes/microglial cells (16) without apparent tumor cell phagocytosis. These monocytic cells may probably be modulated towards chronic inflammatory M2 macrophages. These could promote tumor growth through the production of specific cytokines. Mainly immunosuppressive growth factors like interleukin (IL)-4, IL13 and IL10 have been found in human gliomas, while proinflammatory cytokines like IL12, tumor necrosis factor α (TNFα) or interferon γ (IFN-γ) were absent (17). Moreover, other immunosuppressive factors like CD70, HLA-G or HLA-E (18, 19) – and possibly also other, yet unknown factors - contribute to the immune escape of malignant gliomas (18, 20). On the other hand, immune cells are capable of destroying glioma cells after activation in vitro, indicating that immune therapies might be effective but seem to be inhibited by the immunosuppressive milieu of gliomas (21, 22).

Biology of Galectins Galectins are members of the lectin family of proteins with a high affinity to β-galactosides (23, 24). Today, 15 galectin members have been identified that contain highly conserved carbohydrate-recognition domains (CRD) of about 130 amino acids and are divided into three groups based on the structure of the CRD (25, 26). Like other lectins, galectins are commonly expressed in various tissues and exert a variety of biological functions dependent on their ability to bind intracellular and extracellular glycoconjugates, including extracellular matrix components like laminin or fibronectin (27). Physiologically, galectins are expressed in lymphatic (lymph nodes, thymus, spleen) and epithelial tissues (liver, lung, breast) but also on endothelial cells, brain and inflammatory cells like macrophages (24). As galectins can be localized in the nucleus and/or the cytoplasm (28) as well as on the extracellular cell surface, the biologic effects are heterogeneous, too, ranging from effects on RNA splicing to cell adhesion and survival signaling (27, 29–33). These effects are commonly also linked to oncogenic properties of cells, i.e. enhanced cell proliferation, migration, immune evasion and resistance to apoptotic stimuli (34, 173 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


35). Consequently, enhanced expression of e.g. galectin-1 and galectin-3 has been observed during cancer development and metastasis (36). During malignant progression, a shift in localization from nucleus to cytoplasm has been described for these galectins, too (37). The exact mechanisms, how galectins contribute to malignant transformation and progression are not completely understood but several lines of evidence suggest that galectins can modulate and activate growth-factor related signaling via activation of the Ras-Raf-MAPK and PI3K pathways and regulation of downstream target gene transcription (38, 39). This activation of the survival pathway via MAPK by galectin-3 has also been linked to its anti-apoptotic properties (40). Galectin-3 also has homology to the potent anti-apoptotic molecule bcl-2 and is able to block changes in mitochondrial membrane potential, thus preventing cytochrome c release and intrinsic apoptosis induction (41, 42). Interestingly, galectin-3 does also have pro-apoptotic properties indicating a strong context-dependency of this molecule in cancer cells (43). Angiogenesis is considered a hallmark of tumor growth and prerequisite for metastasis. Galectin-3 has been demonstrated to increase motility of endothelial cells and to promote capillary growth by interaction of galectin-3 with integrins and other cell surface molecules (44–46). This mechanism is also related to the known functions of esp. galectin-3 during cell adhesion and metastasis formation. Here, overexpression of galectin-3 facilitates adhesion to extracellular matrix components (e.g. fibronectin or laminin) or integrins (34, 41, 47). In line with this model, high levels of galectin-3 have been detected in patients with metastatic diseases compared to healthy controls (48). This leads to enhanced adhesion of cancer cells to endothelial cells, supports the aggregation of tumor cells and prevents anoikis during metastatic spread (49, 50). Galectins expressed at the cell surface have been attributed immunosuppressive properties by inducing apoptosis in monocytes and T cells (51) or suppressing production of IL5 (52) and inhibiting differentiation of B cells (34, 53–55). These mechanisms thus contribute to the putative evasion of tumor cells of the immune response. Overall galectins are thus able to promote tumor growth on various levels, i.e. intracellular signaling, extracellular adhesion and matrix interaction and immune surveillance.

Galectins in Malignant Gliomas Several studies demonstrated an overexpression of galectin-1 and galectin3 in various malignant glioma cell lines (56, 57) and in specimens from human tumor samples (58). Galectin levels correlated significantly with angiogenesis, malignant potential and overall survival of glioma patients (59–64). Interestingly, the expression of galectin-1 and galectin-3 is also associated with WHO grading and increases with progression (65, 66). In experimental settings, inhibition of galectins by siRNA lead to decreased proliferation, invasion and angiogenesis (67, 68). Additionally, knockdown of galectin-1 increased the immune rejection of glioma xenografts and also impaired 174 In Galectins and Disease Implications for Targeted Therapeutics; Klyosov, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2012.


the endoplasmic reticulum stress response, leading to enhanced sensitivity towards chemotherapy using temozolomide (69–71). Overall, the biological functions related to galectins as well as the currently available experimental and clinical data give a clear rationale for further development of galectin-inhibiting therapy approaches. The distinct roles of galectins on tumor cells, endothelial cells, extracellular stroma components and immune cells gives the opportunity to target and influence several hallmarks of cancer development and progression simultaneously to achieve improved treatment responses and prolonged overall survival for patients with malignant glioma. An ideal compound to modulate galectins in malignant gliomas would be small-molecular and lipophilic in order to pass the blood-brain barrier and orally available to allow for continuous application and combination with other treatment strategies like conventional chemotherapy.

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Galectins as Novel Targets for the Treatment of Malignant Gliomas

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