Abstract
Sustained tumor angiogenesis, i.e., the induction and maintenance of blood vessel growth by tumor cells, is one of the hallmarks of cancer. The vascularization of malignant tissues not only facilitates tumor growth and metastasis, but also contributes to immune evasion. Important players in all these processes are the endothelial cells which line the luminal side of blood vessel. In the tumor vasculature, these cells are actively involved in angiogenesis as well in the hampered recruitment of immune cells. This is the result of the abnormal tumor microenvironment which triggers both angiostimulatory and immune inhibitory gene expression profiles in endothelial cells. In recent years, it has become evident that galectins constitute a protein family that is expressed in the tumor endothelium. Moreover, several members of this glycan-binding protein family have been found to facilitate tumor angiogenesis and stimulate immune suppression. All this has identified galectins as potential therapeutic targets to simultaneously hamper tumor angiogenesis and alleviate immune suppression. The current review provides a brief introduction in the human galectin protein family. The current knowledge regarding the expression and regulation of galectins in endothelial cells is summarized. Furthermore, an overview of the role that endothelial galectins play in tumor angiogenesis and tumor immunomodulation is provided. Finally, some outstanding questions are discussed that should be addressed by future research efforts. This will help to fully understand the contribution of endothelial galectins to tumor progression and to exploit endothelial galectins for cancer therapy.
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Introduction
The human vasculature is a complex network of blood and lymphatic vessels that facilitate the transport of, amongst others, erythrocytes, leukocytes, thrombocytes and a wide variety of molecules. With a projected length of 100,000 km, the vasculature provides a huge infrastructural system that covers all parts of the human body. All vessels within the vasculature share one important common feature, i.e., their luminal side is composed of endothelial cells. These mesoderm-derived cells form a single cell layer, known as the endothelium, covering the entire inner surface of all vessel walls. It has been estimated that the endothelium comprises over one trillion (> 1 × 1012) endothelial cells, forming a surface area of 300–1000 square meters [1, 2]. This huge interface primarily serves as a barrier between cells and components in the blood and the underlying tissues. However, the endothelial barrier is far from inert and endothelial cells are known to be actively involved in many physiological processes, like regulation of the vascular tone, coagulation, inflammation, and bi-directional transport over the vessel wall [3,4,5,6]. In addition, endothelial cells are indispensable for angiogenesis, i.e., the formation of new blood vessels out of pre-existing vessels. This process is involved in physiological processes like wound healing, inflammation, the menstrual cycle, and pregnancy [3, 7, 8].
Given their widespread presence and diverse functionality, it is not surprising that abnormal endothelial cell activity and aberrant angiogenesis are also associated with different disorders, e.g., rheumatoid arthritis, atherosclerosis, inflammatory disorders, and malignant disease [3, 6, 9, 10]. Regarding the latter, the ability of tumor cells to induce and sustain angiogenesis is considered one of the hallmarks of cancer [11]. Already more than 50 years ago, it was found that most solid tumors become dependent on angiogenesis after reaching a volume 2–3 mm3 [12, 13]. At larger volumes, the high metabolic demand of tumor cells can no longer be fulfilled by diffusion of oxygen and nutrients from existing vessels. As a response, tumor cells start to secrete growth factors that activate endothelial cells in nearby vessels in order to trigger the growth of new blood vessels into the expanding tumor mass. Based on the observed dependency on angiogenesis it has been proposed that targeting tumor blood vessel growth could provide an opportunity for cancer therapy [14]. This insight boosted research into the mechanisms that control tumor angiogenesis and has resulted in the development of numerous angiostatic drugs that are currently used in the clinic [15, 16]. Unfortunately, current angiostatic drugs show only limited clinical benefit due to the development of treatment resistance [17, 18]. Thus, there is still a need to find novel targets and to develop more potent angiostatic drugs.
Over the last three decades, galectins have been identified as key regulators of endothelial cell function and tumor angiogenesis. Moreover, vascular galectins have been found to play a significant role in cancer progression, not only in the context of tumor angiogenesis, but also by suppressing an adequate anti-tumor immune response [19, 20]. This has identified galectins as potential targets for tumor therapy. The current review will first give a general introduction into the human galectin protein family and subsequently summarize the current knowledge regarding the role of vascular galectins in tumor angiogenesis and tumor immune escape.
The galectin protein family
Galectins (formerly known as S-type or S-Lac lectins) represent a subfamily of the animal lectin family [21] and they are defined by structural homology and binding affinity towards β-galactose-containing glycoconjugates [22]. The glycan-binding activity resides in a carbohydrate binding site (CBS) which is located in an evolutionary conserved carbohydrate-recognition domain (CRD) [23]. Generally, the galectin CRD, comprises 120–140 amino acids that fold into a β-sandwich structure consisting of two antiparallel β-sheets of six (S1–S6) and five (F1–F5) β-strands. The overall β-sandwich is curved, creating a 'groove' on the concave side which forms the CBS [24]. The core β-galactose binding occurs within this CBS but structural differences in the CRD and the binding groove further contribute to the glycan-binding affinity and specificity of each galectin (Fig. 1A) [24,25,26]. It is also important to realize that each galectin can bind different glycoconjugates with affinities ranging from millimolar down to nanomolar. This variable affinity depends on glycan composition and complexity [27] but also on the biological context of the glycoconjugate, e.g., in solution or on the cell surface [26]. Moreover, different galectins are subjected to posttranscriptional and posttranslational modifications, like splicing, phosphorylation, and proteolytic cleavage, which can affect their glycan binding and control their biological availability and activity [28,29,30,31,32,33]. Finally, recent studies have shown that the glycan binding can also be altered by peptides and proteins that interact with galectins thereby inducing structural changes in the CRD [34,35,36]. All these findings show that the galectin CRD is not a rigid structure but that it is capable to interact with different glycoconjugates as well as non-glycosylated proteins.
In humans, 15 galectins have been described so far and galectins are generally classified into three subtypes based on the number and organization of the CRDs, (Table 1 + Fig. 1B), i.e., i) prototypical galectins, which consist of a single CRD, ii) tandem-repeat galectins, which have two distinct CRDs connected by a short linker domain, and iii) chimeric galectins, of which only 1 member has been described so far which is characterized by a unique N-terminal domain linked to a single CRD. Galectin functionality is diverse as most galectins can be found both intracellularly as well as in the extracellular environment [25]. However, a key aspect of galectin functionality resides in their ability to dimerize or multimerize. This complex formation increases the binding valency and allows galectins to form 'networks' within or between glycoconjugates [37,38,39]. Consequently, in the extracellular environment galectins can facilitate cell–cell interactions and contribute to cell–matrix adhesion as well as migration (Fig. 1C). Moreover, by clustering cell surface receptors and/or increase receptor surface retention, galectins can modulate signaling (Fig. 1D) [38, 40]. Intracellularly, galectins can also enhance receptor signaling, expedite secretion of cytokines or recognize cytosolic glycoconjugates. Even in the nucleus, galectins have been found to be actively involved in RNA splicing [41,42,43]. It is important to realize that these examples are just a selection of known galectin activities and ongoing research continues to discover new functionalities of this versatile protein family. The current review will further focus on the expression of galectins in the endothelium and their role in tumor angiogenesis and tumor immune evasion.
Endothelial galectin expression
It is well established that multiple galectins are expressed by endothelial cells. In general, out of the 15 galectins found in humans, endothelial cells predominantly express galectin-1, -3, -8, and -9 [44, 45]. Of the latter two, different splice variants can be detected in endothelial cells [44, 46,47,48]. Of the other galectins, only galectin-2, -4, and -12 show some expression at the mRNA level but no detectable protein levels, while the expression of the remaining galectins appears to be completely absent (Fig. 2A) [44]. At the same time, the endothelial expression of galectins is highly variable and depends on different factors, including the specific endothelial cell type, the tissue location as well as environmental conditions. For example, it has been reported that lymphatic endothelial cells show a relatively high expression of galectin-8 [46] while endothelial progenitor cells express relatively high levels of galectin-3 [49]. Such differences are likely related to the environmental conditions in which the endothelial cells reside. For example, irregular blood flow has been shown to trigger endothelial expression of galectin-3 [50]. In line with this, hypoxic conditions have been shown to induce galectin-3 expression in endothelial cells [51]. Other known triggers that affect the expression and/or secretion of galectins by endothelial cells include matrix components, like fibronectin or advanced glycosylation end products [52, 53], inflammatory cytokines like INFγ and TNFα as well as growth factors that induce endothelial activation, like vascular endothelial growth factor (VEGF) (Summarized in Fig. 2B + Table 2) [33, 44, 54,55,56]. Gaining further insight in the regulation of endothelial galectin expression, in particular in the context of the complex tissue microenvironment, remains an ongoing challenge.
Given the abnormal microenvironmental conditions in malignant tissues, it is not surprising that the tumor endothelium displays altered galectin expression compared to normal endothelium. For example, we reported on elevated galectin-1 expression in tumor endothelium vs. normal endothelium in colon carcinoma, breast carcinoma and sarcoma [57]. Others found increased galectin-1 expression in tumor endothelium from oral squamous cell carcinoma [58], prostate cancer [59], lung cancer and head and neck cancer [60]. Likewise, endothelial galectin-3 expression has also been reported in different tumor tissues, e.g., lung [60], head and neck [60], colon [44], and primary central nervous system lymphomas [61]. In the latter, increased endothelial galectin-3 expression was associated with poor patient survival [61]. On the other hand, endothelial galectin-3 expression levels appear to decrease with increasing malignancy in brain tumors [62,63,64]. Moreover, patients with low endothelial galectin-3 expression in primary oligodendrogliomas and anaplastic oligodendrogliomas had significantly shorter progression free and overall survival [63].
With regard to galectin-8, we and others reported that cultured endothelial cells express 3 splice variants [44, 47]. Moreover, activation of cultured endothelial cells by high serum conditions induced a decrease in galectin-8 expression [44]. While this was not further affected by tumor-derived conditioned medium, we did observe an additional reduction in cell surface galectin-8 on endothelial cells after conditioned medium treatment [44]. Of note, in vivo endothelial expression of galectin-8 was only observed in the vasculature of normal colon tissues and sporadically in kidney. When detected, the protein was mainly localized in the nuclei of endothelial cells. In addition, in colon tumor tissues, the frequency of galectin-8 positive endothelial cells was even reduced [44]. Delgado and colleagues also observed clear nuclear galectin-8 expression in blood vessels of both normal and malignant tissues from prostate and breast. Endothelial cells in the prostate also showed cytoplasmic galectin-8 expression, while this was more diffuse in breast tissues [47].
Similar as for galectin-8, endothelial cells have been reported to express different splice variants of galectin-9 [44, 65]. Moreover, the expression and localization of galectin-9 also appears to be regulated by endothelial cell activation status and/or different inflammatory conditions [44, 54, 66]. Endothelial expression of galectin-9 has also been reported to be increased in the tumor vasculature. For example, we observed significantly elevated galectin-9 expression in the tumor endothelium of lung, liver and kidney cancer compared to healthy tissues [31].
Overall, endothelial cells predominantly express galectin-1, -3, -8, and -9. Moreover, in tumor tissues the endothelial expression level and/or localization of these galectins is often different as compared to endothelial cells in normal tissues. This different expression is predominantly triggered by the abnormal tumor microenvironment. Factors that regulate endothelial galectin expression include matrix proteins, growth factors and inflammatory cytokines but also flow and hypoxia. Despite the increasing insights in the regulation of endothelial galectin expression it remains a future challenge to unravel the exact interplay between the tumor microenvironment and galectin expression. Especially since environmental conditions not only influence galectin expression but also affect the expression and composition of glycoconjugates on the endothelial cell surface [67,68,69,70,71]. Moreover, it can be anticipated that the complex regulation of vascular galectins and their ligands by the tumor microenvironment contributes to tumor progression.
Endothelial galectins in tumor progression
As evident from the above, the tumor endothelium is characterized by altered galectin expression. Interestingly, abnormal galectin expression, be it in tumor cells and/or tumor associated stroma, is associated with the diagnosis and/or prognosis of patients with different cancer types [72]. Based on this association, extensive research has been performed to uncover the mechanisms by which galectins contribute to malignant transformation and tumor progression. This has revealed that galectins contribute to most, if not all, hallmarks of cancer [11, 73, 74]. With regard to galectins in the vasculature, research has uncovered different mechanisms by which galectins in the endothelium contribute to tumor progression, including promoting tumor angiogenesis and suppressing the anti-tumor immune response.
Role of vascular galectins in tumor angiogenesis
To understand the role of vascular galectins during tumor angiogenesis, it is important to realize that vessel growth, both under physiological or pathophysiological conditions, is a multistep process during which endothelial cells display different functionalities and behavior. In brief, endothelial cells have to become activated by stimulatory factors that initiate the angiogenic cascade. Once activated, endothelial cells start to remodel the extracellular environment and migrate towards the origin of stimulation. At the same time, cells have to proliferate and organize into tube-like structures in order to form new vessels. All these activities require endothelial cells to interact with the extracellular microenvironment and with other (endothelial) cells. Furthermore, proper execution of these steps involves a concerted action of many different signaling pathways that control the expression and activity of different proteins. Galectins have been identified as one of the key protein families that are involved in angiogenesis by mediating different endothelial cell functions. An overview of their role in angiogenesis was recently presented and is summarized in Fig. 3 [45]. Although not all of the angioregulatory activities of galectins have been identified in the context of malignant disease, it can be anticipated that vascular galectins exert comparable effects on endothelial function during tumor angiogenesis. In line with this, we were the first to show that galectin-1 is essential for tumor vascularization, independent of the tumor type [57, 75]. Furthermore, we and others found that endothelial cells can also exploit extrinsic galectin-1 that is secreted by tumor cells [74,75,76] or cancer associated fibroblasts to increase their angiogenic potential [77].
A key role of galectin-1 in tumor angiogenesis is linked to activation of pro-angiogenic signaling by the vascular endothelial growth factor (VEGF). For example, galectin-1 was described to increase VEGF receptor 2 (VEGFR2) signaling in endothelial cells by facilitating heterodimerization with co-receptor neuropilin-1 (NRP1) [58]. In addition, galectin-1, in combination with galectin-3, was suggested to hamper the internalization of VEGFR1/2 and thereby increasing receptor signaling [78]. Galectin-1 was also linked to VEGFR1/NRP1 complex formation which contributes to vascular permeability in tumors [79]. Compelling evidence linking galectin-1 to VEGFR signaling in tumors was provided by Croci and co-workers. They identified a direct link between VEGFR2 glycosylation and the ability of galectin-1 to activate VEGFR2 signaling. In murine tumors that were non-responsive to anti-VEGF treatment, the altered VEGFR2 glycosylation allowed galectin-1 to activate VEGF-like signaling which contributed to treatment escape [67]. These results also exemplified the important link between endothelial cell glycosylation and their sensitivity to galectins, a link that requires further exploration [68, 76].
Apart from the prominent role in VEGF/VEGFR signaling, ample studies have linked galectin-1 to tumor progression by increasing endothelial cell proliferation and migration, thus facilitating endothelial cell sprouting, tube formation and tumor vascularization [20, 76, 80, 81].
Similar to galectin-1, pro-angiogenic activity has been attributed to galectin-3. As briefly mentioned above, galectin-3 was also found to facilitate VEGFR signaling in endothelial cells [82]. In addition, galectin-3 was found to interact with endoglin, a co-receptor of TGF beta signaling, which is involved in angiogenesis [83]. Galectin-3 also appears to increase endothelial cell adhesion, motility and migration by interacting with different integrins on the cell surface [84,85,86]. In models of breast and pancreas cancer, galectin-3 was shown to trigger endothelial cell functionality in vitro and stimulate tumor angiogenesis in vivo [87,88,89]. Furthermore, part of the angiostimulatory activity of galectin-3 has been linked to the modulation of Notch signaling. It was found that galectin-3 interacts with the Notch ligand JAG1, thereby increasing the half-life of the protein and activating endothelial JAG1/Notch-1 signaling. Consequently, tumor growth in a murine lung tumor model was increased when JAG1 overexpressing tumor cells were used and hampered in galectin-3 knockout mice [69]. Of note, it has been proposed that the angiogenic activity of galectin-3, at least in breast cancer, is dependent on proteolytic cleavage of the galectin-3 N-terminal tail [90]. To what extent full length and cleaved galectin-3 trigger similar or distinct angiostimulatory pathways should be further explored.
More recently, galectin-8 was added to the list of galectins that facilitate VEGF-induced angiogenesis both in vitro and in vivo [91]. Previously, galectin-8 was already found to stimulate endothelial cell migration and tube formation in vitro and angiogenesis in vivo [47]. This activity was linked to interactions of galectin-8 with CD166 (ALCAM; activated leukocyte cell adhesion molecule) [47]. At the same time, galectin-8 was described to interact with different integrins expressed by endothelial cells [92] which could further add to the pro-angiogenic activity. Galectin-8 secreted by tumor cells was also found to induce vascular permeabilization [93], one of the first steps in the endothelial response to pro-angiogenic stimulation [94]. With regard to tumor angiogenesis, it has been described that elevated galectin-8 serum levels, which were observed in breast and colorectal cancer [95], can stimulate endothelial cell tube formation [96]. Thus, similar to galectin-1 and galectin-3, current findings suggests that galectin-8 can stimulate endothelial cell functions but identifying the exact role of the protein in tumor angiogenesis requires further investigation.
With regard to the role of endothelial galectin-9 in tumor angiogenesis also little information is available. As already described above, the tumor endothelium in different cancer types showed elevated galectin-9 expression [31]. However, to what extent the protein contributes to tumor vessel formation is unknown. For example, whether the protein facilitates VEGF/VEGFR signaling -similar as the other endothelial galectins- has not been described. Galectin-9 was found to serve as a chemoattractant for endothelial cells and to stimulate migration and tube formation [33, 97]. At the same time, the effects of galectin-9 appear to be dependent on the activation status of the endothelial cells as well as on the protein isoform and concentration [33]. Regarding the latter, we observed a slight inhibition of in vivo angiogenesis in the chicken chorioallantoic membrane model by galectin-9 at micromolar concentrations while in vitro stimulatory effects were observed at nanomolar concentrations [33]. Since most studies were performed using in vitro models or in the context of developmental angiogenesis, more research is required to further unravel the contribution of endothelial galectin-9 to tumor angiogenesis. The same applies to galectin-12, the latest addition to the list of angioregulatory galectins. Although -again- no information is available in the context of tumor angiogenesis, it was observed that exogenous galectin-12 from adipose tissue can trigger the angiogenic activity of endothelial cells in vitro and in vivo. This was linked to increased availability of fucosylated glycan ligands on endothelial cells under hypoxic conditions [70]. Whether the same mechanism is active in the hypoxic tumor microenvironment awaits further studies. Furthermore, since galectin-12 is not expressed by endothelial cells, these findings warrant investigation into the angioregulatory activity of other galectins that are not expressed by endothelial cells but that do show effects on endothelial cell function, e.g., galectin-2 and galectin-4 [96].
Role of endothelial galectins in tumor immunity
The previous paragraphs summarized how galectins can contribute to tumor progression by regulating endothelial cell activity and tumor angiogenesis. Interestingly, tumor angiogenesis is linked to another hallmark of cancer, i.e., avoiding immune destruction. Indeed, different mechanisms have been described by which angiogenesis, or activated endothelial cells, contribute to immunosuppression, e.g., decreased endothelial expression of leukocyte adhesion molecules as well as increased endothelial expression of immune checkpoint molecules (for excellent recent reviews, see [98, 99]). These mechanisms create a so-called immune-cell barrier at the blood-endothelium interface, and galectins contribute to this barrier by affecting the survival and trafficking of immune cells in the tumor microenvironment. As such, endothelial galectins can be considered as family of proteins that link tumor angiogenesis to tumor immunosuppression [100]. Regarding the immunosuppression, it is important to realize that there is ample evidence of the immunoregulatory activity of galectins in different (patho)physiological processes [73, 101,102,103,104,105,106]. However, not being the scope of the current review to describe these activities in detail, it suffices to state that galectins can trigger a broad range of effects on both lymphoid and myeloid cells by interacting with specific glycoconjugates on the surface of these immune cells. Known effects include -but are not restricted to- recruitment, activation, differentiation, survival of, e.g., B cells, NK cells, regulatory and cytotoxic T cells, dendritic cells, granulocytes, monocytes and macrophages (For comprehensive overviews, see [107, 108]). In general, aberrant galectin expression in tumor cells and/or the tumor microenvironment is considered to contribute to tumor immune escape [105]. In line with this, different mechanisms have been identified by which endothelial galectins might contribute to immunomodulation, albeit not always in the context of malignant disease (Fig. 4) [109, 110]. For example, galectin-1 on the endothelial cell surface has been found to reduce the capture, rolling and adhesion of leukocytes as well as neutrophils on endothelial cells [111, 112]. In addition, endothelial galectin-1 was described to induce apoptosis and hamper transendothelial migration of activated T cells [113, 114]. The latter was linked to clustering of CD43 on T cells thereby interfering with the proper signaling required for migration [113]. In contrast, galectin-1 was found to trigger the migration of dendritic cells by facilitating co-cluster formation of CD43/CD45 [115]. In neutrophils, CD43-galectin-1 interactions as well as galectin-1 induced changes in L-selectin and beta-2 integrin have also been linked to increased neutrophil recruitment and migration [116, 117]. Moreover, galectin-1 stimulated the extravasation of polymorphonuclear leukocytes following lung injury by mediating interactions with endothelial cells [118]. Collectively and comparable to its role in facilitating VEGF receptor signaling during angiogenesis, galectin-1 appears to play an important role in regulating CD43/CD45 functionality, thereby controlling immune cell survival, migration and recruitment. At the same time, it has become evident that these regulatory effects vary between immune cell types and that they are dependent on specific environmental conditions. Thus, while additional research is still warranted, elevated galectin-1 expression in tumor endothelial cells appears to predominantly exert immunosuppressive effects.
The role of endothelial galectin-3 in tumor immunomodulation is still not fully understood but it appears that this family member acts somewhat more ambiguous as compared to galectin-1. In general, galectin-3 within the tumor micro-environment is considered to contribute to immunosuppression [119]. Similar as galectin-1, extracellular galectin-3 has been shown to hamper T cell survival and function, albeit that the exact T cell surface receptors underlying these responses, amongst others, CD7/CD29/CD43/CD45, are still not completely resolved [120, 121]. The interaction between galectin-3 and LAG3 (lymphocyte activation gene 3, CD223) has also been suggested to suppress effector CD8 + T cell function [122] but this also requires further confirmation [123]. Furthermore, whether endothelial cell derived galectin-3 exerts all these immunosuppressive functions at the blood-endothelial interface has not been confirmed yet. What has been described is that galectin-3 mediates the adhesion of neutrophils to endothelial cells. This appears to involve interactions of galectin-3 with ligands on both the neutrophil and the endothelial cell surface [124]. The same appears true for eosinophil-endothelial cell interactions as blocking antibodies that target galectin-3 on either endothelial cells or eosinophils were found to reduce the adhesion and rolling of the latter [125]. More recently, studies in galectin-3 knockout mice confirmed the importance of galectin-3 in decreasing leukocyte rolling and increasing recruitment of neutrophils and monocytes. The latter was linked to induction of an inflammatory environment by exogenous galectin-3 [126]. Since galectin-3 has been suggested to serve as a chemoattractant for monocytes and macrophages [127] it can be speculated that endothelial galectin-3 favors the recruitment and survival of myeloid cells over lymphoid cells. However, the exact contribution of endothelial galectin-3 to tumor immunomodulation still requires further research.
The tandem repeat galectin-8 has also been described to increase leukocyte-endothelial adhesion. In vitro assays revealed enhanced binding of T-cells, B-cells, neutrophils, eosinophils as well as monocytes to HUVEC in the presence of each galectin [128]. The same study also found some adhesion in the presence of either galectin-1 or galectin-3 but the effects were much less pronounced if detected at all. The discrepancies with the previously described roles of both galectin-1 and galectin-3 in leukocyte adhesion are most likely related to the variable experimental conditions regarding the galectin concentration and type of leukocyte or endothelial cells used. In particular, the presence of integrin beta1 appears to be required to facilitate the pro-adhesive function of galectin-8 [128, 129]. Of note, vascular adhesion of multiple myeloma cells (malignant cells of B cell origin) was also enhanced by galectin-8 [48]. Thus, galectin-8 appears to be involved in leukocyte trafficking. Next to this activity, galectin-8 was also found to induce direct proinflammatory effects by inducing the expression of proinflammatory cytokines in endothelial cells [130], activating dendritic cells [131] and increasing T cell proliferation [132]. However, the latter was only observed for naïve T cells while galectin-8 induced cell death of activated T cells [132], in line with the other galectins.
Galectin-9, the other tandem repeat galectin that is expressed by endothelial cells, has also been linked to increased leukocyte-endothelial adhesion. This includes similar populations as those linked to galectin-8-mediated adhesion, e.g., T cells, B cells, neutrophils and monocytes [128]. In addition, recent studies have provided additional insight in the specific activity of galectin-9 in leukocyte-endothelial interactions. For example, galectin-9, but not galectin-1 or -3, was shown to increase the adhesion of B cells to endothelial cells. However, the trans-endothelial migration was not affected and galectin-9 was found to trigger signaling indicative of B cell anergy [55]. The adhesion of CD14 + monocytes to activated endothelial cells (poly I:C stimulation) was also facilitated by galectin-9 while the transmigration was not [56]. In addition, the galectin-9 mediated monocyte adhesion appeared to be dependent on integrin beta2 (CD18) [56], an interaction that was also linked to the endothelial capture and adhesion of neutrophils and T cells [133, 134]. Regarding the latter, galectin-9 was reported to facilitate the adhesion to and migration over stimulated endothelial cells (TNF-α/IFN-γ) of both CD4 + and CD8 + T cells. Consequently, in an in vivo model of leukocyte recruitment (dorsal air pouch model), galectin-9 knockout mice showed hampered leukocyte trafficking [134]. Of note, it has also been suggested that Jurkat cells (immortalized human T cells) use galectin-9 for adhesion by interacting with blood group H glycans on the endothelial cell surface [135]. In addition, galectin-9 was reported to interact with protein disulfide isomerase on the T cell surface which promotes cell migration [136, 137]. Apparently, galectin-9 contributes to different mechanisms that regulate the recruitment and trafficking of leukocytes in the vasculature.
While the observed activities indicate an immunostimulatory function there is increasing interest in the immunosuppressive activity of galectin-9, in particular in the context of tumor immune escape. The immunosuppressive function is partly related to the ability of galectin-9 to bind TIM3 (T cell immunoglobulin and mucin domain containing protein 3) which is presented on the surface of different immune cells. The TIM-3/galectin-9 interaction alters TIM-3 signaling leading to immune cell anergy or apoptosis (for a recent review, see [138]). As such, the TIM3/galectin-9 signaling axis shows similarities with more 'classic' immune checkpoints like PD1/PD-L1 or CTLA-4/CD80 [138, 139]. Interestingly, it was shown that galectin-9 can also interact with PD-1 thereby attenuating galectin-9/TIM-3-induced apoptosis of exhausted CD8 + T cells in tumors [104]. Moreover, galectin-1 has been shown to induce tumor immune exclusion by increasing the endothelial expression of checkpoint molecules like PD-L1 as well as galectin-9 [140]. This supports the concept that endothelial galectins jointly act in creating an immunosuppressive environment. In line with this, galectins have been proposed to serve as immune checkpoint proteins that can be targeted for treatment of cancer [139].
Summary and future directions
It is well recognized that the abnormal conditions in the tumor microenvironment affect the endothelial transcriptome [141,142,143]. As summarized here, the altered expression includes different galectins, predominantly galectin-1/-3/-8/-9. Moreover, the cellular localization, secretion and function of these endothelial galectins can be affected under malignant conditions. While different environmental triggers underlying the aberrant endothelial galectin expression have already been identified, it remains a challenge to unravel the mechanisms that control galectin expression and localization within the tumor vasculature. In addition, more insight in the mechanisms that regulate the endothelial glycome is necessary since alteration in protein glycosylation on the endothelial cell surface will affect the functional consequences of galectins [26, 67, 110]. Thus, further deciphering the galectin-glycan networks and linking these to endothelial cell activity remains an important future challenge.
Regarding the role of galectins in the tumor vasculature, the current literature predominantly suggests a tumor-promoting role by facilitation of both tumor angiogenesis and tumor immune escape. At the same time, there are still many unresolved questions regarding the exact mechanisms that underlie this angiostimulatory and immunosuppressive activity. Importantly, most studies have been performed using a single galectin or a specific immune cell type. Since the tumor microenvironment is far more complex, it can be anticipated that the activity of a given galectin on a given cell type is affected by the presence of other cells or other extracellular factors. For example, emerging evidence from us and others has shown that galectins can heterodimerize with other galectins, cytokines or growth factors, thereby controlling the activity of either protein [36, 39, 134, 144,145,146]. In addition, the expression and/or secretion of such molecules by different cell types within the tumor microenvironment will influence the ability of galectins to control endothelial or immune cell functionality. This is further complicated by the observation that galectins can show biphasic activity depending on the local concentration or activation status of the target cell [33, 114, 132, 147]. Deciphering such complex relationships remains challenging. In that regard, the development of animal models that allow conditional and (endothelial) cell specific knockdown of galectins or glycosylation pathways will be indispensable. Also, the current developments in (single cell) RNA sequencing as well as in spatial transcriptomics will help to uncover the role of (vascular) galectins the complex tumor microenvironment [148,149,150].
Despite the outstanding challenges, vascular galectins are considered as potential targets for cancer treatment. In fact, galectins are generally considered as potential therapeutic targets and many different galectin inhibitors have been developed, some of which have been tested in clinical trials (For a comprehensive recent review see [151]). Interestingly, endothelial cells are particularly attractive target cells since they are in direct contact with the blood and therefore easy reached by circulating drugs [3]. Moreover, targeting galectins in the vasculature could have dual benefit by simultaneously hampering tumor angiogenesis and alleviating immune suppression. This is supported by numerous studies showing that targeting galectins can hamper tumor progression by interfering with tumor vascularization and/or by stimulating an anti-tumor immune response [57, 140, 152,153,154,155,156,157,158]. For example, we recently published that vaccination against galectin-1 can increase tumor infiltration of cytotoxic CD8 + T cells resulting in reduced tumor growth [159]. Also recently, a novel set of orally available galectin-1 inhibitors was published that blocked the induction of T cell (Jurkat) apoptosis by galectin-1 [160]. Collectively, the continuous development of novel compounds and approaches to target galectins in combination with the unceasing efforts to unravel the mechanisms by which galectins contribute to tumor progression hold a promise for the treatment of future cancer patients. In particular since targeting endothelial galectins can have dual effects by inhibiting tumor angiogenesis and at the same time stimulating the anti-tumor immune response. This identifies galectins as interesting 'new kids on the therapeutic block'.
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References
Jaffe EA (1987) Cell biology of endothelial cells. Hum Pathol 18:234–239. https://doi.org/10.1016/s0046-8177(87)80005-9
Pries AR, Secomb TW, Gaehtgens P (2000) The endothelial surface layer. Pflugers Arch 440:653–666. https://doi.org/10.1007/s004240000307
Griffioen AW, Molema G (2000) Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev 52:237–268
Galley HF, Webster NR (2004) Physiology of the endothelium. Br J Anaesth 93:105–113. https://doi.org/10.1093/bja/aeh163
Aird WC (2012) Endothelial cell heterogeneity. Cold Spring Harb Perspect Med 2:a006429. https://doi.org/10.1101/cshperspect.a006429
Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P, Han J, Harding IC, Ebong EE, Cameron SJ, Stewart AG, Weng J (2021) Endothelial dysfunction in atherosclerotic cardiovascular diseases and beyond: from mechanism to pharmacotherapies. Pharmacol Rev 73:924–967. https://doi.org/10.1124/pharmrev.120.000096
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873–887
Aird WC (2007) Phenotypic heterogeneity of the endothelium: II Representative vascular beds. Circ Res 100:174–190. https://doi.org/10.1161/01.RES.0000255690.03436.ae
Carmeliet P, Jain RK (2011) Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov 10:417–427. https://doi.org/10.1038/nrd3455
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674
Folkman J, Cole P, Zimmerman S (1966) Tumor behavior in isolated perfused organs: in vitro growth and metastases of biopsy material in rabbit thyroid and canine intestinal segment. Ann Surg 164:491–502
Folkman J, Merler E, Abernathy C, Williams G (1971) Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133:275–288
Folkman J (1972) Anti-angiogenesis: new concept for therapy of solid tumors. Ann Surg 175:409–416
Lugano R, Ramachandran M, Dimberg A (2020) Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci 77:1745–1770. https://doi.org/10.1007/s00018-019-03351-7
Hamming LC, Slotman BJ, Verheul HMW, Thijssen VL (2017) The clinical application of angiostatic therapy in combination with radiotherapy: past, present, future. Angiogenesis 20:217–232. https://doi.org/10.1007/s10456-017-9546-9
Huijbers EJM, van Beijnum JR, Thijssen VL, Sabrkhany S, Nowak-Sliwinska P, Griffioen AW (2016) Role of the tumor stroma in resistance to anti-angiogenic therapy. Drug Resist Updat 25:26–37. https://doi.org/10.1016/j.drup.2016.02.002
van Beijnum JR, Nowak-Sliwinska P, Huijbers EJM, Thijssen VL, Griffioen AW (2015) The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev 67:441–461. https://doi.org/10.1124/pr.114.010215
Thijssen VL, Poirier F, Baum LG, Griffioen AW (2007) Galectins in the tumor endothelium; opportunities for combined cancer therapy. Blood 110:2819–2827. https://doi.org/10.1182/blood-2007-03-077792
Thijssen VL, Rabinovich GA, Griffioen AW (2013) Vascular galectins: regulators of tumor progression and targets for cancer therapy. Cytokine Growth Factor Rev 24:547–558. https://doi.org/10.1016/j.cytogfr.2013.07.003
Vasta GR, Ahmed H (2009) Introduction to animal lectins. In: Vasta GR, Ahmed H (eds) Animal lectins: a functional view, CRC press, Boca Raton, pp 3–9
Barondes SH, Cooper DN, Gitt MA, Leffler H (1994) Galectins Structure and function of a large family of animal lectins. J Biol Chem 269:20807–20810
Houzelstein D, Goncalves IR, Fadden AJ, Sidhu SS, Cooper DN, Drickamer K, Leffler H, Poirier F (2004) Phylogenetic analysis of the vertebrate galectin family. Mol Biol Evol 21:1177–1187
Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004) Introduction to galectins. Glycoconj J 19:433–440
Johannes L, Jacob R, Leffler H (2018) Galectins at a glance. J Cell Sci 131:jcs208884. https://doi.org/10.1242/jcs.208884
Nielsen MI, Stegmayr J, Grant OC, Yang Z, Nilsson UJ, Boos I, Carlsson MC, Woods RJ, Unverzagt C, Leffler H, Wandall HH (2018) Galectin binding to cells and glycoproteins with genetically modified glycosylation reveals galectin-glycan specificities in a natural context. J Biol Chem 293:20249–20262. https://doi.org/10.1074/jbc.RA118.004636
Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, Urashima T, Oka T, Futai M, Muller WE, Yagi F, Kasai K (2002) Oligosaccharide specificity of galectins: a search by frontal affinity chromatography. Biochim Biophys Acta 1572:232–254
Mazurek N, Conklin J, Byrd JC, Raz A, Bresalier RS (2000) Phosphorylation of the beta-galactoside-binding protein galectin-3 modulates binding to its ligands. J Biol Chem 275:36311–36315. https://doi.org/10.1074/jbc.M003831200
Nishi N, Itoh A, Shoji H, Miyanaka H, Nakamura T (2006) Galectin-8 and galectin-9 are novel substrates for thrombin. Glycobiology 16:15C-20C. https://doi.org/10.1093/glycob/cwl028
Balan V, Nangia-Makker P, Kho DH, Wang Y, Raz A (2012) Tyrosine-phosphorylated galectin-3 protein is resistant to prostate-specific antigen (PSA) cleavage. J Biol Chem 287:5192–5198. https://doi.org/10.1074/jbc.C111.331686
Heusschen R, Schulkens IA, van Beijnum J, Griffioen AW, Thijssen VL (2014) Endothelial LGALS9 splice variant expression in endothelial cell biology and angiogenesis. Biochim Biophys Acta 1842:284–292. https://doi.org/10.1016/j.bbadis.2013.12.003
Gao X, Liu J, Liu X, Li L, Zheng J (2017) Cleavage and phosphorylation: important post-translational modifications of galectin-3. Cancer Metastasis Rev 36:367–374. https://doi.org/10.1007/s10555-017-9666-0
Aanhane E, Schulkens IA, Heusschen R, Castricum K, Leffler H, Griffioen AW, Thijssen VL (2018) Different angioregulatory activity of monovalent galectin-9 isoforms. Angiogenesis 21:545–555. https://doi.org/10.1007/s10456-018-9607-8
Salomonsson E, Thijssen VL, Griffioen AW, Nilsson UJ, Leffler H (2011) The anti-angiogenic peptide anginex greatly enhances galectin-1 binding affinity for glycoproteins. J Biol Chem 286:13801–13804. https://doi.org/10.1074/jbc.C111.229096
Bonzi J, Bornet O, Betzi S, Kasper BT, Mahal LK, Mancini SJ, Schiff C, Sebban-Kreuzer C, Guerlesquin F, Elantak L (2015) Pre-B cell receptor binding to galectin-1 modifies galectin-1/carbohydrate affinity to modulate specific galectin-1/glycan lattice interactions. Nat Commun 6:6194. https://doi.org/10.1038/ncomms7194
Sanjurjo L, Schulkens IA, Touarin P, Heusschen R, Aanhane E, Castricum KCM, De Gruijl TD, Nilsson UJ, Leffler H, Griffioen AW, Elantak L, Koenen RR, Thijssen VLJL (2021) Chemokines modulate glycan binding and the immunoregulatory activity of galectins. Commun Biol 4:1415. https://doi.org/10.1038/s42003-021-02922-4
Earl LA, Bi S, Baum LG (2011) Galectin multimerization and lattice formation are regulated by linker region structure. Glycobiology 21:6–12
Rabinovich GA, Toscano MA, Jackson SS, Vasta GR (2007) Functions of cell surface galectin-glycoprotein lattices. Curr Opin Struct Biol 17:513–520
Dings RPM, Kumar N, Mikkelson S, Gabius HJ, Mayo KH (2021) Simulating cellular galectin networks by mixing galectins in vitro reveals synergistic activity. Biochem Biophys Rep 28:101116. https://doi.org/10.1016/j.bbrep.2021.101116
Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL, Dennis JW (2004) Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306:120–124
Godefa TM, Derks S, Thijssen VLJL (2022) Galectins in esophageal cancer: current knowledge and future perspectives. Cancers (Basel) 14:5790. https://doi.org/10.3390/cancers14235790
Wei J, Li DK, Hu X, Cheng C, Zhang Y (2021) Galectin-1-RNA interaction map reveals potential regulatory roles in angiogenesis. FEBS Lett 595:623–636. https://doi.org/10.1002/1873-3468.14047
Wei J, Wu Y, Sun Y, Chen D (2023) Galectin-1 regulates RNA expression and alternative splicing of angiogenic genes in HUVECs. Front Biosci (Landmark Ed) 28:74. https://doi.org/10.31083/j.fbl2804074
Thijssen VL, Hulsmans S, Griffioen AW (2008) The galectin profile of the endothelium: altered expression and localization in activated and tumor endothelial cells. Am J Pathol 172:545–553. https://doi.org/10.2353/ajpath.2008.070938
Thijssen VL (2021) Galectins in endothelial cell biology and angiogenesis: the basics. Biomolecules 11:1386. https://doi.org/10.3390/biom11091386
Cueni LN, Detmar M (2009) Galectin-8 interacts with podoplanin and modulates lymphatic endothelial cell functions. Exp Cell Res 315:1715–1723
Cardenas Delgado VM, Nugnes LG, Colombo LL, Troncoso MF, Fernandez MM, Malchiodi EL, Frahm I, Croci DO, Compagno D, Rabinovich GA, Wolfenstein-Todel C, Elola MT (2011) Modulation of endothelial cell migration and angiogenesis: a novel function for the “tandem-repeat” lectin galectin-8. Faseb J 25:242–254
Friedel M, André S, Goldschmidt H, Gabius HJ, Schwartz-Albiez R (2016) Galectin-8 enhances adhesion of multiple myeloma cells to vascular endothelium and is an adverse prognostic factor. Glycobiology 26:1048–1058. https://doi.org/10.1093/glycob/cww066
Furuhata S, Ando K, Oki M, Aoki K, Ohnishi S, Aoyagi K, Sasaki H, Sakamoto H, Yoshida T, Ohnami S (2007) Gene expression profiles of endothelial progenitor cells by oligonucleotide microarray analysis. Mol Cell Biochem 298:125–138
Garcia-Cardena G, Comander J, Anderson KR, Blackman BR, Gimbrone MA Jr (2001) Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci U S A 98:4478–4485
Li Y, Chen X, Zeng X, Chen S, Yang X, Zhang L (2020) Galectin-3 mediates pulmonary vascular endothelial cell dynamics via TRPC1/4 under acute hypoxia. J Biochem Mol Toxicol 34:e22463. https://doi.org/10.1002/jbt.22463
Ahrens I, Domeij H, Topcic D, Haviv I, Merivirta RM, Agrotis A, Leitner E, Jowett JB, Bode C, Lappas M, Peter K (2011) Successful in vitro expansion and differentiation of cord blood derived CD34+ cells into early endothelial progenitor cells reveals highly differential gene expression. PLoS ONE 6:e23210. https://doi.org/10.1371/journal.pone.0023210
Deo P, Glenn JV, Powell LA, Stitt AW, Ames JM (2009) Upregulation of oxidative stress markers in human microvascular endothelial cells by complexes of serum albumin and digestion products of glycated casein. J Biochem Mol Toxicol 23:364–372
Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, Nishi N, Fujimoto K, Tanji K, Shibata T, Tamo W, Matsumiya T, Yoshida H, Cui X-F, Takanashi S, Hanada K, Okumura K, Yagihashi S, Wakabayashi K, Nakamura T, Hirashima M, Satoh K (2002) Interferon-{gamma} stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol 72:486–491
Chakraborty A, Staudinger C, King SL, Erickson FC, Lau LS, Bernasconi A, Luscinskas FW, Perlyn C, Dimitroff CJ (2021) Galectin-9 bridges human B cells to vascular endothelium while programming regulatory pathways. J Autoimmun 117:102575. https://doi.org/10.1016/j.jaut.2020.102575
Krautter F, Hussain MT, Zhi Z, Lezama DR, Manning JE, Brown E, Marigliano N, Raucci F, Recio C, Chimen M, Maione F, Tiwari A, McGettrick HM, Cooper D, Fisher EA, Iqbal AJ (2022) Galectin-9: A novel promoter of atherosclerosis progression. Atherosclerosis 363:57–68. https://doi.org/10.1016/j.atherosclerosis.2022.11.014
Thijssen VL, Postel R, Brandwijk RJ, Dings RP, Nesmelova I, Satijn S, Verhofstad N, Nakabeppu Y, Baum LG, Bakkers J, Mayo KH, Poirier F, Griffioen AW (2006) Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy. Proc Natl Acad Sci U S A 103:15975–15980. https://doi.org/10.1073/pnas.0603883103
Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY, Jin YT, Hong TM, Chen YL (2008) Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27:3746–3753
Clausse N, van den Brule F, Waltregny D, Garnier F, Castronovo V (1999) Galectin-1 expression in prostate tumor-associated capillary endothelial cells is increased by prostate carcinoma cells and modulates heterotypic cell-cell adhesion. Angiogenesis 3:317–325
Lotan R, Belloni PN, Tressler RJ, Lotan D, Xu XC, Nicolson GL (1994) Expression of galectins on microvessel endothelial cells and their involvement in tumour cell adhesion. Glycoconj J 11:462–468
D’Haene N, Catteau X, Maris C, Martin B, Salmon I, Decaestecker C (2008) Endothelial hyperplasia and endothelial galectin-3 expression are prognostic factors in primary central nervous system lymphomas. Br J Haematol 140:402–410. https://doi.org/10.1111/j.1365-2141.2007.06929.x
Strik HM, Deininger MH, Frank B, Schluesener HJ, Meyermann R (2001) Galectin-3: cellular distribution and correlation with WHO-grade in human gliomas. J Neurooncol 53:13–20
Deininger MH, Trautmann K, Meyermann R, Schluesener HJ (2002) Galectin-3 labeling correlates positively in tumor cells and negatively in endothelial cells with malignancy and poor prognosis in oligodendroglioma patients. Anticancer Res 22:1585–1592
Gordower L, Decaestecker C, Kacem Y, Lemmers A, Gusman J, Burchert M, Danguy A, Gabius H, Salmon I, Kiss R, Camby I (1999) Galectin-3 and galectin-3-binding site expression in human adult astrocytic tumours and related angiogenesis. Neuropathol Appl Neurobiol 25:319–330
Spitzenberger F, Graessler J, Schroeder HE (2001) Molecular and functional characterization of galectin 9 mRNA isoforms in porcine and human cells and tissues. Biochimie 83:851–862
Alam S, Li H, Margariti A, Martin D, Zampetaki A, Habi O, Cockerill G, Hu Y, Xu Q, Zeng L (2011) Galectin-9 protein expression in endothelial cells is positively regulated by histone deacetylase 3. J Biol Chem 286:44211–44217
Croci DO, Cerliani JP, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, Toscano MA, Caramelo JJ, García-Vallejo JJ, Ouyang J, Mesri EA, Junttila MR, Bais C, Shipp MA, Salatino M, Rabinovich GA (2014) Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in Anti-VEGF refractory tumors. Cell 156:744–758. https://doi.org/10.1016/j.cell.2014.01.043
Croci DO, Cerliani JP, Pinto NA, Morosi LG, Rabinovich GA (2014) Regulatory role of glycans in the control of hypoxia-driven angiogenesis and sensitivity to anti-angiogenic treatment. Glycobiology 24:1283–1290. https://doi.org/10.1093/glycob/cwu083
Dos Santos SN, Sheldon H, Pereira JX, Paluch C, Bridges EM, El-Cheikh MC, Harris AL, Bernardes ES (2017) Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/Notch activation. Oncotarget 8:49484–49501. https://doi.org/10.18632/oncotarget.17718
Maller SM, Cagnoni AJ, Bannoud N, Sigaut L, Pérez Sáez JM, Pietrasanta LI, Yang RY, Liu FT, Croci DO, Di Lella S, Sundblad V, Rabinovich GA, Mariño KV (2020) An adipose tissue galectin controls endothelial cell function via preferential recognition of 3-fucosylated glycans. FASEB J 34:735–753. https://doi.org/10.1096/fj.201901817R
García-Vallejo JJ, Van Dijk W, Van Het Hof B, Van Die I, Engelse MA, Van Hinsbergh VWM, Gringhuis SI (2006) Activation of human endothelial cells by tumor necrosis factor-alpha results in profound changes in the expression of glycosylation-related genes. J Cell Physiol 206:203–210. https://doi.org/10.1002/jcp.20458
Thijssen VL, Heusschen R, Caers J, Griffioen AW (2015) Galectin expression in cancer diagnosis and prognosis: a systematic review. Biochim Biophys Acta 1855:235–247. https://doi.org/10.1016/j.bbcan.2015.03.003
Girotti MR, Salatino M, Dalotto-Moreno T, Rabinovich GA (2020) Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression. J Exp Med 217:e20182041. https://doi.org/10.1084/jem.20182041
Videla-Richardson GA, Morris-Hanon O, Torres NI, Esquivel MI, Vera MB, Ripari LB, Croci DO, Sevlever GE, Rabinovich GA (2021) Galectins as emerging glyco-checkpoints and therapeutic targets in glioblastoma. Int J Mol Sci 23:316. https://doi.org/10.3390/ijms23010316
Thijssen VL, Barkan B, Shoji H, Aries IM, Mathieu V, Deltour L, Hackeng TM, Kiss R, Kloog Y, Poirier F, Griffioen AW (2010) Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res 70:6216–6224. https://doi.org/10.1158/0008-5472.CAN-09-4150
Croci DO, Salatino M, Rubinstein N, Cerliani JP, Cavallin LE, Leung HJ, Ouyang J, Ilarregui JM, Toscano MA, Domaica CI, Croci MC, Shipp MA, Mesri EA, Albini A, Rabinovich GA (2012) Disrupting galectin-1 interactions with N-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in Kaposi’s sarcoma. J Exp Med 209:1985–2000. https://doi.org/10.1084/jem.20111665
Tang D, Gao J, Wang S, Ye N, Chong Y, Huang Y, Wang J, Li B, Yin W, Wang D (2015) Cancer-associated fibroblasts promote angiogenesis in gastric cancer through galectin-1 expression. Tumour Biol.https://doi.org/10.1007/s13277-015-3942-9
D’Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C, Baum L, Salmon I (2013) VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. PLoS ONE 8:e67029. https://doi.org/10.1371/journal.pone.0067029
Wu MH, Ying NW, Hong TM, Chiang WF, Lin YT, Chen YL (2014) Galectin-1 induces vascular permeability through the neuropilin-1/vascular endothelial growth factor receptor-1 complex. Angiogenesis 17:839–849. https://doi.org/10.1007/s10456-014-9431-8
Laderach DJ, Gentilini LD, Giribaldi L, Delgado VC, Nugnes L, Croci DO, Al Nakouzi N, Sacca P, Casas G, Mazza O, Shipp MA, Vazquez E, Chauchereau A, Kutok JL, Rodig SJ, Elola MT, Compagno D, Rabinovich GA (2013) A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease. Cancer Res 73:86–96. https://doi.org/10.1158/0008-5472.CAN-12-1260
van Beijnum JR, Thijssen VL, Läppchen T, Wong TJ, Verel I, Engbersen M, Schulkens IA, Rossin R, Grüll H, Griffioen AW, Nowak-Sliwinska P (2016) A key role for galectin-1 in sprouting angiogenesis revealed by novel rationally designed antibodies. Int J Cancer. https://doi.org/10.1002/ijc.30131
Markowska AI, Jefferies KC, Panjwani N (2011) Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. J Biol Chem 286:29913–29921
Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, Quintanilla M, Bernabeu C (2019) Endoglin protein interactome profiling identifies TRIM21 and galectin-3 as new binding partners. Cells 8:E1082. https://doi.org/10.3390/cells8091082
Fukushi J, Makagiansar IT, Stallcup WB (2004) NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol Biol Cell 15:3580–3590
Wesley UV, Vemuganti R, Ayvaci ER, Dempsey RJ (2013) Galectin-3 enhances angiogenic and migratory potential of microglial cells via modulation of integrin linked kinase signaling. Brain Res 1496:1–9. https://doi.org/10.1016/j.brainres.2012.12.008
Sedlář A, Trávníčková M, Bojarová P, Vlachová M, Slámová K, Křen V, Bačáková L (2021) Interaction between galectin-3 and integrins mediates cell-matrix adhesion in endothelial cells and mesenchymal stem cells. Int J Mol Sci 22:5144. https://doi.org/10.3390/ijms22105144
Califice S, Castronovo V, Bracke M, van den Brule F (2004) Dual activities of galectin-3 in human prostate cancer: tumor suppression of nuclear galectin-3 vs tumor promotion of cytoplasmic galectin-3. Oncogene 23:7527–7536
Nangia-Makker P, Balan V, Raz A (2008) Regulation of tumor progression by extracellular galectin-3. Cancer Microenviron 1:43–51. https://doi.org/10.1007/s12307-008-0003-6
Nangia-Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ, Raz A (2000) Galectin-3 induces endothelial cell morphogenesis and angiogenesis. Am J Pathol 156:899–909
Nangia-Makker P, Wang Y, Raz T, Tait L, Balan V, Hogan V, Raz A (2010) Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. Int J Cancer 127:2530–2541
Varinská L, Fáber L, Petrovová E, Balážová L, Ivančová E, Kolář M, Gál P (2020) Galectin-8 favors VEGF-induced angiogenesis. In vitro study in human umbilical vein endothelial cells and in vivo study in chick chorioallantoic membrane. Anticancer Res 40:3191–3201. https://doi.org/10.21873/anticanres.14300
Hadari YR, Arbel-Goren R, Levy Y, Amsterdam A, Alon R, Zakut R, Zick Y (2000) Galectin-8 binding to integrins inhibits cell adhesion and induces apoptosis. J Cell Sci 113:2385–2397
Zamorano P, Koning T, Oyanadel C, Mardones GA, Ehrenfeld P, Boric MP, González A, Soza A, Sánchez FA (2019) Galectin-8 induces endothelial hyperpermeability through the eNOS pathway involving S-nitrosylation-mediated adherens junction disassembly. Carcinogenesis 40:313–323. https://doi.org/10.1093/carcin/bgz002
Dvorak HF (2015) Tumor stroma, tumor blood vessels, and antiangiogenesis therapy. Cancer J 21:237–243. https://doi.org/10.1097/PPO.0000000000000124
Barrow H, Guo X, Wandall HH, Pedersen JW, Fu B, Zhao Q, Chen C, Rhodes JM, Yu LG (2011) Serum galectin-2, -4, and -8 are greatly increased in colon and breast cancer patients and promote cancer cell adhesion to blood vascular endothelium. Clin Cancer Res 17:7035–7046. https://doi.org/10.1158/1078-0432.CCR-11-1462
Chen C, Duckworth CA, Fu B, Mark Pritchard D, Rhodes JM, Yu L-G (2014) Circulating galectins -2, -4 and -8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis. Br J Cancer.https://doi.org/10.1038/bjc.2013.793
O’Brien MJ, Shu Q, Stinson WA, Tsou PS, Ruth JH, Isozaki T, Campbell PL, Ohara RA, Koch AE, Fox DA, Amin MA (2018) A unique role for galectin-9 in angiogenesis and inflammatory arthritis. Arthritis Res Ther 20:31. https://doi.org/10.1186/s13075-018-1519-x
Khan KA, Kerbel RS (2018) Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol 15:310–324. https://doi.org/10.1038/nrclinonc.2018.9
Huinen ZR, Huijbers EJM, van Beijnum JR, Nowak-Sliwinska P, Griffioen AW (2021) Anti-angiogenic agents - overcoming tumour endothelial cell anergy and improving immunotherapy outcomes. Nat Rev Clin Oncol 18:527–540. https://doi.org/10.1038/s41571-021-00496-y
Méndez-Huergo SP, Blidner AG, Rabinovich GA (2017) Galectins: emerging regulatory checkpoints linking tumor immunity and angiogenesis. Curr Opin Immunol 45:8–15. https://doi.org/10.1016/j.coi.2016.12.003
Blidner AG, Méndez-Huergo SP, Cagnoni AJ, Rabinovich GA (2015) Re-wiring regulatory cell networks in immunity by galectin-glycan interactions. FEBS Lett 589:3407–3418. https://doi.org/10.1016/j.febslet.2015.08.037
Sundblad V, Morosi LG, Geffner JR, Rabinovich GA (2017) Galectin-1: A jack-of-all-trades in the resolution of acute and chronic inflammation. J Immunol 199:3721–3730. https://doi.org/10.4049/jimmunol.1701172
Rabinovich GA, Toscano MA (2009) Turning ‘sweet’ on immunity: galectin-glycan interactions in immune tolerance and inflammation. Nat Rev Immunol 9:338–352
Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, Yan M, Chang WC, Hsu JM, Cha JH, Hsu JL, Chou CW, Sun X, Deng Y, Chou CK, Yu D, Hung MC (2021) Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun 12:832. https://doi.org/10.1038/s41467-021-21099-2
Mariño KV, Cagnoni AJ, Croci DO, Rabinovich GA (2023) Targeting galectin-driven regulatory circuits in cancer and fibrosis. Nat Rev Drug Discov. https://doi.org/10.1038/s41573-023-00636-2
Hisrich BV, Young RB, Sansone AM, Bowens Z, Green LJ, Lessey BA, Blenda AV (2020) Role of human galectins in inflammation and cancers associated with endometriosis. Biomolecules 10:230. https://doi.org/10.3390/biom10020230
Cerliani JP, Blidner AG, Toscano MA, Croci DO, Rabinovich GA (2017) Translating the ‘sugar code’ into immune and vascular signaling programs. Trends Biochem Sci 42:255–273. https://doi.org/10.1016/j.tibs.2016.11.003
Elola MT, Ferragut F, Méndez-Huergo SP, Croci DO, Bracalente C, Rabinovich GA (2018) Galectins: Multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment. Cell Immunol 333:34–45. https://doi.org/10.1016/j.cellimm.2018.03.008
Thiemann S, Baum LG (2010) The Road Less Traveled: regulation of leukocyte migration across vascular and lymphatic endothelium by galectins. J Clin Immunol
Lightfoot A, McGettrick HM, Iqbal AJ (2021) Vascular Endothelial Galectins in Leukocyte Trafficking. Front Immunol 12:687711. https://doi.org/10.3389/fimmu.2021.687711
Norling LV, Sampaio AL, Cooper D, Perretti M (2008) Inhibitory control of endothelial galectin-1 on in vitro and in vivo lymphocyte trafficking. Faseb J 22:682–690
Cooper D, Norling LV, Perretti M (2008) Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. J Leukoc Biol 83:1459–1466
He J, Baum LG (2006) Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab Invest 86:578–590
Perillo NL, Pace KE, Seilhamer JJ, Baum LG (1995) Apoptosis of T cells mediated by galectin-1. Nature 378:736–739
Fulcher JA, Chang MH, Wang S, Almazan T, Hashimi ST, Eriksson AU, Wen X, Pang M, Baum LG, Singh RR, Lee B (2009) Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling. J Biol Chem 284:26860–26870. https://doi.org/10.1074/jbc.M109.037507
Auvynet C, Moreno S, Melchy E, Coronado-Martínez I, Montiel JL, Aguilar-Delfin I, Rosenstein Y (2013) Galectin-1 promotes human neutrophil migration. Glycobiology 23:32–42. https://doi.org/10.1093/glycob/cws128
Gil CD, Gullo CE, Oliani SM (2010) Effect of exogenous galectin-1 on leukocyte migration: modulation of cytokine levels and adhesion molecules. Int J Clin Exp Pathol 4:74–84
Feng C, Cross AS, Vasta GR (2023) Galectin-1 mediates interactions between polymorphonuclear leukocytes and vascular endothelial cells, and promotes their extravasation during lipopolysaccharide-induced acute lung injury. Mol Immunol 156:127–135. https://doi.org/10.1016/j.molimm.2023.02.011
Gilson RC, Gunasinghe SD, Johannes L, Gaus K (2019) Galectin-3 modulation of T-cell activation: mechanisms of membrane remodelling. Prog Lipid Res 76:101010. https://doi.org/10.1016/j.plipres.2019.101010
Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H, Kagawa S, Raz A (2003) CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res 63:8302–8311
Stillman BN, Hsu DK, Pang M, Brewer CF, Johnson P, Liu FT, Baum LG (2006) Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J Immunol 176:778–789
Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, Jaffee E (2015) Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res 3:412–423. https://doi.org/10.1158/2326-6066.CIR-14-0150
Aggarwal V, Workman CJ, Vignali DAA (2023) LAG-3 as the third checkpoint inhibitor. Nat Immunol 24:1415–1422. https://doi.org/10.1038/s41590-023-01569-z
Sato S, Ouellet N, Pelletier I, Simard M, Rancourt A, Bergeron MG (2002) Role of galectin-3 as an adhesion molecule for neutrophil extravasation during streptococcal pneumonia. J Immunol 168:1813–1822
Rao SP, Wang Z, Zuberi RI, Sikora L, Bahaie NS, Zuraw BL, Liu FT, Sriramarao P (2007) Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion under conditions of flow. J Immunol 179:7800–7807
Gittens BR, Bodkin JV, Nourshargh S, Perretti M, Cooper D (2017) Galectin-3: a positive regulator of leukocyte recruitment in the inflamed microcirculation. J Immunol 198:4458–4469. https://doi.org/10.4049/jimmunol.1600709
Sano H, Hsu DK, Yu L, Apgar JR, Kuwabara I, Yamanaka T, Hirashima M, Liu FT (2000) Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J Immunol 165:2156–2164. https://doi.org/10.4049/jimmunol.165.4.2156
Yamamoto H, Nishi N, Shoji H, Itoh A, Lu LH, Hirashima M, Nakamura T (2008) Induction of cell adhesion by galectin-8 and its target molecules in Jurkat T-cells. J Biochem 143:311–324
Carcamo C, Pardo E, Oyanadel C, Bravo-Zehnder M, Bull P, Caceres M, Martinez J, Massardo L, Jacobelli S, Gonzalez A, Soza A (2006) Galectin-8 binds specific beta1 integrins and induces polarized spreading highlighted by asymmetric lamellipodia in Jurkat T cells. Exp Cell Res 312:374–386
Cattaneo V, Tribulatti MV, Carabelli J, Carestia A, Schattner M, Campetella O (2014) Galectin-8 elicits pro-inflammatory activities in the endothelium. Glycobiology 24:966–973. https://doi.org/10.1093/glycob/cwu060
Carabelli J, Quattrocchi V, D’Antuono A, Zamorano P, Tribulatti MV, Campetella O (2017) Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation. J Leukoc Biol 102:1237–1247. https://doi.org/10.1189/jlb.3A0816-357RR
Cattaneo V, Tribulatti MV, Campetella O (2011) Galectin-8 tandem-repeat structure is essential for T-cell proliferation but not for co-stimulation. Biochem J 434:153–160. https://doi.org/10.1042/BJ20101691
Iqbal AJ, Krautter F, Blacksell IA, Wright RD, Austin-Williams SN, Voisin MB, Hussain MT, Law HL, Niki T, Hirashima M, Bombardieri M, Pitzalis C, Tiwari A, Nash GB, Norling LV, Cooper D (2022) Galectin-9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin-dependent manner. FASEB J 36:e22065. https://doi.org/10.1096/fj.202100832R
Mansour AA, Raucci F, Sevim M, Saviano A, Begum J, Zhi Z, Pezhman L, Tull S, Maione F, Iqbal AJ (2022) Galectin-9 supports primary T cell transendothelial migration in a glycan and integrin dependent manner. Biomed Pharmacother 151:113171. https://doi.org/10.1016/j.biopha.2022.113171
Rapoport EM, Ryzhov IM, Slivka EV, Korchagina EY, Popova IS, Khaidukov SV, André S, Kaltner H, Gabius HJ, Henry S, Bovin NV (2023) Galectin-9 as a potential modulator of lymphocyte adhesion to endothelium via binding to blood group H glycan. Biomolecules 13:1166. https://doi.org/10.3390/biom13081166
Bi S, Hong PW, Lee B, Baum LG (2011) Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci 108:10650–10655. https://doi.org/10.1073/pnas.1017954108
Schaefer K, Webb NE, Pang M, Hernandez-Davies JE, Lee KP, Gonzalez P, Douglass MV, Lee B, Baum LG (2017) Galectin-9 binds to O-glycans on protein disulfide isomerase. Glycobiology 27:878–887. https://doi.org/10.1093/glycob/cwx065
Wolf Y, Anderson AC, Kuchroo VK (2020) TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol 20:173–185. https://doi.org/10.1038/s41577-019-0224-6
Compagno D, Tiraboschi C, Garcia JD, Rondón Y, Corapi E, Velazquez C, Laderach DJ (2020) Galectins as checkpoints of the immune system in cancers, their clinical relevance, and implication in clinical trials. Biomolecules 10:E750. https://doi.org/10.3390/biom10050750
Nambiar DK, Aguilera T, Cao H, Kwok S, Kong C, Bloomstein J, Wang Z, Rangan VS, Jiang D, von Eyben R, Liang R, Agarwal S, Colevas AD, Korman A, Allen CT, Uppaluri R, Koong AC, Giaccia A, Le QT (2019) Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J Clin Invest. https://doi.org/10.1172/JCI129025
Wang W, Wang L, She J, Zhu J (2021) Examining heterogeneity of stromal cells in tumor microenvironment based on pan-cancer single-cell RNA sequencing data. Cancer Biol Med 19:30–42. https://doi.org/10.20892/j.issn.2095-3941.2020.0762
van Beijnum JR, Huijbers EJM, van Loon K, Blanas A, Akbari P, Roos A, Wong TJ, Denisov SS, Hackeng TM, Jimenez CR, Nowak-Sliwinska P, Griffioen AW (2022) Extracellular vimentin mimics VEGF and is a target for anti-angiogenic immunotherapy. Nat Commun 13:2842. https://doi.org/10.1038/s41467-022-30063-7
Qian J, Olbrecht S, Boeckx B, Vos H, Laoui D, Etlioglu E, Wauters E, Pomella V, Verbandt S, Busschaert P, Bassez A, Franken A, Bempt MV, Xiong J, Weynand B, van Herck Y, Antoranz A, Bosisio FM, Thienpont B, Floris G, Vergote I, Smeets A, Tejpar S, Lambrechts D (2020) A pan-cancer blueprint of the heterogeneous tumor microenvironment revealed by single-cell profiling. Cell Res 30:745–762. https://doi.org/10.1038/s41422-020-0355-0
Gordon-Alonso M, Hirsch T, Wildmann C, van der Bruggen P (2017) Galectin-3 captures interferon-gamma in the tumor matrix reducing chemokine gradient production and T-cell tumor infiltration. Nat Commun 8:793. https://doi.org/10.1038/s41467-017-00925-6
Eckardt V, Miller MC, Blanchet X, Duan R, Leberzammer J, Duchene J, Soehnlein O, Megens RT, Ludwig AK, Dregni A, Faussner A, Wichapong K, Ippel H, Dijkgraaf I, Kaltner H, Döring Y, Bidzhekov K, Hackeng TM, Weber C, Gabius HJ, von Hundelshausen P, Mayo KH (2020) Chemokines and galectins form heterodimers to modulate inflammation. EMBO Rep e47852. https://doi.org/10.15252/embr.201947852
Gedaj A, Zukowska D, Porebska N, Pozniak M, Krzyscik M, Czyrek A, Krowarsch D, Zakrzewska M, Otlewski J, Opalinski L (2023) Short report galectins use N-glycans of FGFs to capture growth factors at the cell surface and fine-tune their signaling. Cell Commun Signal 21:122. https://doi.org/10.1186/s12964-023-01144-x
Hillenmayer A, Wertheimer CM, Geerlof A, Eibl KH, Priglinger S, Priglinger C, Ohlmann A (2022) Galectin-1 and -3 in high amounts inhibit angiogenic properties of human retinal microvascular endothelial cells in vitro. PLoS ONE 17:e0265805. https://doi.org/10.1371/journal.pone.0265805
Xu N, Wang X, Wang L, Song Y, Zheng X, Hu H (2022) Comprehensive analysis of potential cellular communication networks in advanced osteosarcoma using single-cell RNA sequencing data. Front Genet 13:1013737. https://doi.org/10.3389/fgene.2022.1013737
Li C, Guo H, Zhai P, Yan M, Liu C, Wang X, Shi C, Li J, Tong T, Zhang Z, Ma H, Zhang J (2024) Spatial and single-cell transcriptomics reveal a cancer-associated fibroblast subset in HNSCC that restricts infiltration and antitumor activity of CD8+ T Cells. Cancer Res 84:258–275. https://doi.org/10.1158/0008-5472.CAN-23-1448
Baysoy A, Bai Z, Satija R, Fan R (2023) The technological landscape and applications of single-cell multi-omics. Nat Rev Mol Cell Biol 24:695–713. https://doi.org/10.1038/s41580-023-00615-w
Laderach DJ, Compagno D (2022) Inhibition of galectins in cancer: Biological challenges for their clinical application. Front Immunol 13:1104625. https://doi.org/10.3389/fimmu.2022.1104625
Stannard KA, Collins PM, Ito K, Sullivan EM, Scott SA, Gabutero E, Darren Grice I, Low P, Nilsson UJ, Leffler H, Blanchard H, Ralph SJ (2010) Galectin inhibitory disaccharides promote tumour immunity in a breast cancer model. Cancer Lett 299:95–110. https://doi.org/10.1016/j.canlet.2010.08.005
Li H, Wang Y, Zhou F (2010) Effect of ex vivo-expanded γδ-T cells combined with galectin-1 antibody on the growth of human cervical cancer xenografts in SCID mice. Clin Invest Med 33:E280–E289
Dings RP, Van Laar ES, Loren M, Webber J, Zhang Y, Waters SJ, Macdonald JR, Mayo KH (2010) Inhibiting tumor growth by targeting tumor vasculature with galectin-1 antagonist anginex conjugated to the cytotoxic acylfulvene, 6-hydroxylpropylacylfulvene. Bioconjug Chem 21:20–27
Ito K, Scott SA, Cutler S, Dong LF, Neuzil J, Blanchard H, Ralph SJ (2011) Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress. Angiogenesis 14:293–307
Dalotto-Moreno T, Croci DO, Cerliani JP, Martinez-Allo VC, Dergan-Dylon S, Méndez-Huergo SP, Stupirski JC, Mazal D, Osinaga E, Toscano MA, Sundblad V, Rabinovich GA, Salatino M (2013) Targeting galectin-1 overcomes breast cancer-associated immunosuppression and prevents metastatic disease. Cancer Res 73:1107–1117. https://doi.org/10.1158/0008-5472.CAN-12-2418
Koonce NA, Griffin RJ, Dings RPM (2017) Galectin-1 inhibitor OTX008 induces tumor vessel normalization and tumor growth inhibition in human head and neck squamous cell carcinoma models. Int J Mol Sci 18(12):2671. https://doi.org/10.3390/ijms18122671
Wdowiak K, Francuz T, Gallego-Colon E, Ruiz-Agamez N, Kubeczko M, Grochoła I, Wojnar J (2018) Galectin targeted therapy in oncology: current knowledge and perspectives. Int J Mol Sci 19:E210. https://doi.org/10.3390/ijms19010210
Femel J, van Hooren L, Herre M, Cedervall J, Saupe F, Huijbers EJM, Verboogen DRJ, Reichel M, Thijssen VL, Griffioen AW, Hellman L, Dimberg A, Olsson AK (2022) Vaccination against galectin-1 promotes cytotoxic T-cell infiltration in melanoma and reduces tumor burden. Cancer Immunol Immunother 71:2029–2040. https://doi.org/10.1007/s00262-021-03139-4
Zetterberg FR, Diehl C, Håkansson M, Kahl-Knutson B, Leffler H, Nilsson UJ, Peterson K, Roper JA, Slack RJ (2023) Discovery of selective and orally available galectin-1 inhibitors. J Med Chem 66(24):16980–16990. https://doi.org/10.1021/acs.jmedchem.3c01787
Seal RL, Braschi B, Gray K, Jones TEM, Tweedie S, Haim-Vilmovsky L, Bruford EA (2023) Genenames.org: the HGNC resources in 2023. Nucleic Acids Res 51:D1003–D1009. https://doi.org/10.1093/nar/gkac888
Pranjol MZI, Zinovkin DA, Maskell ART, Stephens LJ, Achinovich SL, Los’ DM, Nadyrov EA, Hannemann M, Gutowski NJ, Whatmore JL (2019) Cathepsin L-induced galectin-1 may act as a proangiogenic factor in the metastasis of high-grade serous carcinoma. J Transl Med 17:216.https://doi.org/10.1186/s12967-019-1963-7
Gil CD, La M, Perretti M, Oliani SM (2006) Interaction of human neutrophils with endothelial cells regulates the expression of endogenous proteins annexin 1, galectin-1 and galectin-3. Cell Biol Int 30:338–344
Ishikawa A, Imaizumi T, Yoshida H, Nishi N, Nakamura T, Hirashima M, Satoh K (2004) Double-stranded RNA enhances the expression of galectin-9 in vascular endothelial cells. Immunol Cell Biol 82:410–414
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Thijssen, V.L.J.L. Vascular galectins in tumor angiogenesis and cancer immunity. Semin Immunopathol 46, 3 (2024). https://doi.org/10.1007/s00281-024-01014-9
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DOI: https://doi.org/10.1007/s00281-024-01014-9