Open access peer-reviewed chapter
Abstract
Angiogenesis is a pivotal point in tumor progression driven by firmly orchestrated process of forming the new blood vessels relying on the complex signaling network. Here, the pleiotropic functions of Galectin-3 and IL-17 in tumor progression have been overviewed through their impacts on angiogenesis. As a key player in tumor microenvironment, Galectin-3 orchestrates practically all critical events during angiogenic cascade through interaction with various ligands and their downstream signaling pathways. Galectin-3 shapes chronic inflammatory tumor microenvironment that is closely related to angiogenesis by sharing common signaling cascades and molecules. In chronic inflammatory makeup of tumor microenvironment, IL-17 contributes to tumorigenesis and progression via promoting critical events such as angiogenesis and creation of immunosuppressive milieu. VEGF, as the master regulator of tumor angiogenesis, is the main target of Galectin-3 and IL-17 action. The better understanding of Galectin-3 and IL-17 in tumor biology will undoubtedly contribute to controlling tumor progression. Therefore, as important modulators of tumor angiogenesis, Galectin-3 and IL-17 may be perceived as the potential therapeutic targets in tumor including anti-angiogenic therapy.
Keywords
- galectin-3
- IL-17
- VEGF
- tumor angiogenesis
- tumor progression
1. Introduction
Tumor angiogenesis or aberrant vascularization is considered a critical hallmark of tumor progression that is inevitable for tumor growth and metastatic spread [1]. This complex multistep process of new vasculature formation from pre-existing blood vessels is triggered by numerous signals from tumor cells in a phase of rapid growth [1]. The expression and secretion of various activators and inhibitors of angiogenesis are regulated by gene mutation (e.g., oncogenes and tumor-suppressor genes), and microenvironmental factors such as hypoxia and accumulation of different metabolites [2, 3]. As the growing tumor requires more blood vessels for nutrition and oxygen supply, angiogenic pathways are induced by tilting the balance toward pro-angiogenic molecules (angiogenic switch) to drive new blood vessel growth [3].
High expression levels of pro-angiogenic factors reflect the tumor aggressiveness [4]. Within the angiogenic cascade, a diverse group of mediators are shown in Figure 1. These molecules participate in the establishment of new tumor vessels in various ways. Among them, vascular endothelial growth factor (VEGF), also called VEGF-A, is key “molecular player” that modifies the endothelial barriers [3]. Moreover, VEGF as master regulator of angiogenesis in tumor tissues and its receptors, particularly VEGFR-2, have been implicated in tumor vascularization [3]. Namely, activation of VEGF/VEGFR-2 signaling pathways triggers an angiogenic program in the endothelial cells (ECs) [3]. Thus, VEGF binds to its cognate receptor that results in autophosphorylation of specific tyrosine residues of VEGFR-2, and consequential activation of multiple downstream signaling networks in the vascular endothelial cells through the recruiting of the MAP kinase (ERK1/2 and p38), PI3K, AKT, PLC-γ, and JAK-STAT [5, 6, 7]. The final result is the activation of full range of biological responses that modulate angiogenesis, including vascular permeability as well as endothelial cell proliferation, survival, adhesion, and migration.
Figure 1.
Pro-angiogenic mediators implicated in the tumor angiogenesis. Plethora of mediators that promotes tumor angiogenesis can be categorized into several groups. VEGFs-vascular endothelial factors; FGFs-fibroblast growth factors; PDGFs-platelet-derived growth factor; EGFs-epidermal growth factor; TGFs-transforming growth factors; MMPs-matrix metalloproteinases; uPA-urokinase-type plasminogen activator; TNF-α-tumor necrosis factor-α; NO-nitric oxide; PGE2-prostaglandin E2; S1P-sphingosine-1-phosphate.
It is well established that VEGF is multifunctional molecule. VEGF has been first identified as vascular permeability factor, which exerts potent ability to increase vascular permeability, resulting in leakage of plasma protein and other molecules out of blood vessels [8]. Furthermore, VEGF is a potent mitogen that is highly specific for ECs and stimulates cell proliferation through VEGFR-2-mediated activation of the RAS/RAF/ERK/MAPK pathway [9]. Acting as survival factor for ECs, VEGF increases expression of the anti-apoptotic proteins Bcl-2 and A1 in the ECs [10]. On the other hand, VEGF also participates in tumor angiogenesis through increased migration and invasion of ECs by enhancing of matrix metalloproteinases (MMPs) release [3], and further amplifying angiogenesis by enhanced recruitment and homing of bone marrow derived vascular precursor cells [11]. PI3K/AKT signaling promotes VEGF-mediated invasion and metastasis of ECs [12].
VEGF expression is tightly regulated by plethora of transcriptional regulators, such as transcription factor called hypoxia-inducible factor (HIF). Beside them, VEGF signaling is also upregulated by multiple stimuli, including cytokines and galectins by tumor microenvironments. We discuss the role of IL-17 and Galectin-3 in mediating angiogenesis, either directly or indirectly
2. Galectin-3 and IL-17: an important piece in the puzzle of tumor microenvironment
The tumor microenvironment represents a complex ecosystem involving interactions between tumor cells, ECs, epithelial cells, immune cells, fibroblasts, and the extracellular matrix, as well as secreted cytokines and growth factors. All of these factors provide essential support for the tumor progression. The dynamic cross-talk between angiogenesis and tumor microenvironment is important to further accelerate tumor growth and metastasis [13]. Thus, released angiogenic factors can promote tumor immunosuppression by inhibiting maturation of dendritic cells, increasing mobilization of immunosuppressive cells, and suppressing CD8 + T cell activity [14]. The tumor microenvironment, in turn, produces numerous soluble molecules and growth factors that stimulate angiogenesis, thus forming a vicious circle for tumor progression [15]. Increasing evidence suggests that Galectin-3 and IL-17 are the significant pieces of that puzzle that shape angiogenesis and tumor progression in many ways (Figure 2).
Figure 2.
Pro-angiogenic effects of Galectin-3 and IL-17 as a part of tumor progression machinery. Many cells and soluble mediators create tumor microenvironment characterized by hypoxia, chronic inflammation, and immunosuppression. Galectin-3 participates in all steps of angiogenic cascade
Galectin-3, a unique chimaera-type member of the lectin family with selectivity for β-galactosides, is a versatile galectin involved in fundamental biological processes as well as various pathological circumstances [16, 17]. This evolutionary conserved molecule is usually overexpressed in variety types of tumor [18]. The ECs, immune cells, mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), and myofibroblasts also produce and secrete Galectin-3 [19, 20, 21]. Galectin-3 expression is higher in endothelial progenitor cells as compared with normal ECs [22]. However, the tumor microenvironment, for example, tumor cells, inflammatory cells, and/or specific glycan-ligands on galectin-binding proteins, alters endothelial Galectin-3 expression as it provide most of the signals to which the ECs respond [23, 24]. Accordingly, pro-inflammatory cytokine IL-1β increases Galectin-3 expression by ECs [25]. ECs not only have a pivotal role in angiogenesis, but also they facilitate tumor invasion by secreting growth factors and extracellular matrix proteinases [26]. Released molecules sequentially increase chances that tumor cells enter to the circulation and metastasis [26].
Depending on cell types and cellular localization, Galectin-3 drives force in the diverse processes critical in tumor biology, including apoptosis, invasion, metastasis, immune surveillance, gene expression, and inflammation [27]. The cytoplasmic Galectin-3 blocks apoptotic machinery in tumor cells [16] through several mechanisms [28]. Galectin-3 secreted by tumor cells contributes to immunosuppression within the tumor microenvironment by polarizing to pro-tumor phenotype of tumor-associated macrophages 2 (TAM2), restricting T cell receptor clustering, and triggering apoptosis of CD8 + T lymphocytes, further facilitating tumor escape [29]. The upregulation of Galectin-3 by TAMs in the hypoxic regions of breast cancer promotes tumor cell migration and invasion and TAMs-mediated metastasis, as well as angiogenesis [30]. Expression of Galectin-3 in CAFs in breast cancer has been associated with distant metastasis [31]. Galectin-3 is also found in extracellular vesicles released by tumor cells, and it seems that this galectin is critical regulator in cell-cell and cell-extracellular matrix interactions [32]. Endothelial Galectin-3 expression in the lungs cooperates with poly-N-acetyl-lactosamine on N-glycans of B16-F1 murine melanoma cells, as a ligand for Galectin-3 [33]. Our data demonstrated that host-derived Galectin-3 facilitates B16-F1 cell adhesion to the metastatic target and interferes with efficiency of the antitumor immune response, thereby accelerating melanoma metastasis [34].
Tumor angiogenesis and chronic inflammation are closely related and often share common signaling pathways and molecules [35]. In addition to angiogenesis, Galectin-3 participates in shaping of tumor inflammatory microenvironment likely through the recruitment of inflammatory cells and modification of their polarization [36], as well as the production of pro-inflammatory cytokines that have been implicated in tumor promotion (Figure 2, [37]). Overexpressed pro-inflammatory IL-1, IL-6, and TNF-α contribute to various steps of tumor progression [38]. This cytokine network, required for the establishment of chronic inflammation in the tumor microenvironment, facilitates tumor growth and metastasis, enhances angiogenesis, and inhibits immune surveillance [39]. In particular, tumor-infiltrating Th17 lymphocytes orchestrate the maintenance of chronic inflammation. IL-6, TGF-β, and IL-1β are pivotal drivers of development of Th17 cells that secrete IL-17 and other cytokines. Although IL-23 is not required for triggering Th17 differentiation, it is essential for the function, survival, and expansion of Th17 lymphocytes in the inflamed tissue [40]. To increase inflammation, IL-17 induces mobilization, recruitment, and activation of different immune cells [40]. Interestingly, the finding of correlation between serum Galectin-3 levels and IL-17 production in patients with colorectal carcinoma has suggested that Galectin-3 may be one of the important modulators in the regulation of inflammatory conditions (Figure 2, [41]).
IL-17A (commonly referred to as IL-17) is the first discovered and best characterized member of the IL-17 family. Currently, six structurally related cytokines of IL-17 family have been identified (IL-17A to IL-17F) [42]. It is well documented that IL-17 plays protective role in infections, but here, we will review the multifunctional impacts of IL-17 on tumor biology.
IL-17 is mostly produced and secreted by Th17 lymphocytes, but it can be also produced by a broad spectrum of other cell populations [42]. Many studies describe the Th17-rich microenvironment in various types of tumor and that Th17 lymphocytes are endowed with a unique functional plasticity [40, 43]. Tumor cells, CAFs, and myeloid-derived suppressor cells (MDSCs) have been found to produce cytokine milieu that elicits recruitment and/or generation of Th17 lymphocytes [44, 45]. In addition, metabolic conditions present in the tumor milieu including indoleamine 2,3-dioxygenase (IDO) and hypoxia drive the differentiation of CD4 + T lymphocytes toward the Th17 lineage [46, 47]. Type 17 CD8 + T cytotoxic (Tc17) lymphocytes among tumor-infiltrating lymphocytes (TILs) were detected in nasopharyngeal [48] and gastric cancer [49]. Further, the main IL-17-producing cells in breast cancer are tumor-infiltrating γδT cells [50], and it seems that these TILs can promote the breast cancer progression [51]. NKT cells and group 3 innate lymphoid cells (ILC3s) represent other innate lymphocytes capable to produce IL-17 in the tumor microenvironment [52]. On the other hand, IL-17R is widely expressed in ECs, epithelial cells, fibroblasts, hematopoietic cells [53], and tumor cells [54], which implicates pleiotropic effects of IL-17 in the tumor microenvironment.
It seems that IL-17, as Roman god Janus, exerts two opposite faces in the tumor: “dark face” that drives tumor progression and “light face” responsible for the development of effective antitumor immunity. By
3. Galectin-3 as a tumor angiogenesis virtuoso
The critical events during angiogenic cascade such as activation, proliferation, and migration of ECs, as well as sprouting and tube formation, largely depend on Galectin-3 [66]. Initially, it has been observed that soluble Galectin-3 affects the migration of human umbilical vein endothelial cells (HUVECs) and capillary tube formation indicating its potential as chemoattractant for ECs [19]. This result has been confirmed by the increased tumor angiogenesis in the presence of Galectin-3
Ever since, Galectin-3 has been widely recognized as powerful pro-angiogenic molecule acting through various receptors on the ECs, subsequently activating distinct signaling pathways involved in tumor angiogenesis (Figure 2). Interactions between Galectin-3 and different integrins expressed on ECs supposed to be critical in controlling endothelial cell migration and adhesion. Pericyte-derived neural/glial antigen 2 (NG2) proteoglycan, Galectin-3, and α3β1 integrin form the membrane complex that triggers intracellular signaling involved in endothelial cell motility [69]. The blocking antibodies specific for αVβ3, α5β1, and α2β1 integrins interfere with endothelial cell adhesion to Galectin-3-coated surface [70]. In addition to integrins, Galectin-3 on endothelial cell migration markedly depends on direct binding to the membrane highly glycosylated cell adhesion molecule CD146, also known as melanoma cell adhesion molecule [71]. CD146 has been recognized as VEGFR-2 co-receptor and a potential target for anti-angiogenic therapy in tumors [72]. The interaction between Galectin-3 and CD146 is also responsible for secretion of pro-metastatic cytokines by ECs indicating that this axis regulates distinct events during tumor progression [73]. Galectin-3 interacts with glycoprotein endoglin expressed predominantly by ECs as a component of TGF-β receptor complex [74]. Endoglin is abundantly expressed by proliferating ECs indicating an important role of TGF-β/endoglin signaling in tumor vasculature formation [75]. Therefore, thanks to its carbohydrate-binding capacity, Galectin-3 interacts with different molecules expressed by ECs in tumor microenvironment. Moreover, truncated Galectin-3, containing CRD domain, interacts more efficiently with ECs in comparison with full-length molecule [76, 77]. Apart from CRD domain, it seems that angiostimulatory effect of Galectin-3 also depends on its N-terminal tail [78]. Full-length Galectin-3, including its ability to oligomerize through N-terminal domain, appears to be necessary to affect migration of ECs and capillary tube formation [78]. Taken together, angiostimulatory effect of Galectin-3 on distinct events during angiogenesis has been mediated by different parts of the molecule in both carbohydrate dependent and independent manner [68].
Further investigation of the molecular mechanisms responsible for Galectin-3 pro-angiogenic actions in tumors documented its involvement in modulation of VEGF and basic fibroblast growth factor (bFGF) signaling pathways. Galectin-3 binds N-glycans of integrin αvβ3
Galectin-3 has been described as a regulator of Jagged-1 (JAG1)/NOTCH1 signaling axis involved in tumor vasculature formation, in particular sprouting angiogenesis [83]. Under hypoxic condition, secreted Galectin-3 directly binds Notch ligand JAG1 in ECs thus activating pro-angiogenic JAG1/NOTCH1 signaling pathway. Galectin-3 prolongs the half-life of JAG1 over the Delta-like-4 (DLL4) thus affecting the balance between these molecules with opposite functions during angiogenic cascade [83, 84]. Interestingly, the proposed mechanism seems to be independent of VEGF/VEGFR signaling thus revealing novel potential targets in anti-angiogenic therapy.
In addition, Galectin-3 promotes the progression of hepatocellular carcinoma, including angiogenesis, through upregulation of β-catenin signaling [85]. Given its presence in different cellular compartments including nucleus, as well as its pleiotropic functions, Galectin-3 interferes with β-catenin pathway known to be active in various types of tumor. Galectin-3 activates PI3K/AKT signaling thus enhancing the phosphorylation and inactivation of key molecule of β-catenin degradation complex known as glycogen synthase kinase-3β (GSK-3β) [85, 86]. Subsequently, β-catenin accumulates in the nucleus and regulates the expression of genes involved in Galectin-3-mediated angiogenesis and epithelial-mesenchymal transition (EMT) [85].
Exosomes are vesicles secreted by living cells that participate in intercellular communication during essential processes such as proliferation, apoptosis, migration, and angiogenesis [87]. A highly glycosylated protein named lectin galactoside-binding soluble 3 binding protein (LGALS3BP), as a ligand for Galectin-3, has been previously recognized as a modulator of breast cancer angiogenesis that elevates VEGF expression via PI3K/AKT signaling pathway [88]. It has been shown recently that exosomes highly containing LGALS3BP affect endometrial cancer growth and angiogenesis [89]. The exosomes delivering LGALS3BP induce tumor cell proliferation and migration and HUVEC angiogenesis by triggering PI3K/AKT/VEGF signaling pathway [89].
The complex interplay between immunosuppression and angiogenesis is the integral part of tumor progression [29]. TAMs are the critical participants in tumor progression involved in the creation of immunosuppressive microenvironment thus enhancing metastasis and angiogenesis [90]. TAMs produce various pro-angiogenic molecules including growth factors (e.g., VEGF), chemokines, cytokines, as well as MMPs [90]. Galectin-3 promotes alternative activation of TAMs toward their pro-tumorigenic M2 phenotype (Figure 2, [29]). Increased angiogenesis in tumor is strongly associated with macrophage influx driven by elevated Galectin-3 expression [36]. Furthermore, Galectin-3 deficiency in both tumor tissue and stroma impairs angiogenesis
Collectively, thanks to its distinctive structure, Galectin-3 engages plenty of ligands both intracellularly and extracellularly, further interfering with various signaling pathways that regulate tumor angiogenesis. As a potential orchestrator of angiogenic cascade, Galectin-3 may be successfully targeted for anti-angiogenic tumor therapy.
4. Cytokine regulation of tumor angiogenesis: pro-angiogenic activity of IL-17
Apart from galectins, certain cytokine network within the tumor microenvironment contributes to angiogenesis mainly through sophisticated interplay between different cells and extracellular matrix components as well as stimulation of key pro-angiogenic mediator productions.
The data from human subjects have indicated the strong association between increased angiogenicity and high frequency of tumor-infiltrating Th17 lymphocytes [92, 93]. IL-17 overexpression has been associated with higher microvascular density (MVD) in tumors [92]. In general, IL-17 indirectly amplifies angiogenesis mostly by inducing VEGF upregulation, as well as another angiogenic factors by tumor cells and CAFs [94, 95, 96]. Also, IL-17 induces the recruitment of inflammatory cells with angiogenic phenotype (e.g., macrophages and neutrophils) and immunosuppressive cells to the tumor microenvironment, which contributes to different points of angiogenesis in many ways (Figure 2, [59, 97]). Even though the IL-17 overexpression has been detected in tumors, mechanisms of IL-17 that contribute to angiogenesis are still unclear. IL-17/IL-17RA axis promotes the activation of JAK-STAT3 signaling pathway resulting in phosphorylation and nuclear translocation of STAT3 [98]. STAT3 is important regulator of VEGF expression [96]. Furthermore, IL-17-mediated tumor angiogenesis involves the activation of STAT3/GIV (Gα-interacting vesicle-associated protein, Girdin) signaling pathway and subsequent upregulation of its downstream target VEGF [99]. Wu et al. [96] determined that IL-17 induces VEGF upregulation and neovascularization through STAT3-mediated signaling pathway in tumor cells that could be blocked by JSI-124, an inhibitor of phosphorylated STAT3. In addition, other mediators such as granulocyte colony-stimulating factor (G-CSF), EGF, FGF, PDGF, and IL-6 exhibit their pro-angiogenic functions
IL-17 stimulates the production of IL-8 [102]. IL-8 acts directly on ECs by promoting their proliferation, survival, and migration, as well as indirectly by increasing the recruitment of neutrophils that are important source of angiogenic factors in tumor microenvironment [103]. IL-17 activates ECs to produce pro-inflammatory chemokines and cytokines, including CXCL1, IL-8, and granulocyte macrophage-colony-stimulating factor (GM-CSF), thus promoting neutrophil recruitment and adhesion to ECs [98]. It is well known that neutrophils release plethora of molecules that promotes angiogenesis. In particular, neutrophil-derived MMP-9 is critical for catalyzing angiogenic switch in tumor cells and releasing of sequestered growth factors (e.g., VEGF), as well as remodeling of extracellular matrix (ECM) components during angiogenesis [104].
Accumulation of neutrophils has been associated with higher MVD and therefore more aggressive phenotype of gastric cancer [105]. IL-17 enhances the production of many angiogenic CXC chemokines including CXCL1, CXCL5, CXCL6, and CXCL8 (IL-8) [106, 107]. Among these, CXCL1 and CXCL5 are the important chemoattractants for neutrophils [108]. The listed chemokines also promote CXCR2-dependent angiogenesis by stimulating the migration and proliferation of ECs [107]. On the other hand, IL-17 facilitates recruitment and activation of MDSCs in tumor microenvironment [109]. Apart from immunosuppressive activity, MDSCs modulate angiogenesis
Increased IL-17 and IL-23 mRNA expression has been associated with invasive gastric cancer [111]. We have shown that serum levels of IL-17 and IL-23 are significantly elevated in patients with colorectal carcinoma, but only IL-23 significantly correlated with overexpression of VEGF [112, 113]. It seems that IL-23 induces tumor-associated inflammation and angiogenesis thus promoting tumor growth [114]. IL-23-induced differentiation of Th17 lymphocytes suggests the possible indirect role of IL-23 in angiogenesis in IL-17-dependent manner (Figure 2).
There is evidence of tightly relationship between IL-17 and IL-33. Serum IL-33 has been associated with elevated IL-17 levels in patients with autoimmune hepatitis [115]. In addition, intestinal epithelial cells-derived IL-33 stimulates the recruitment of Th17 lymphocytes as the main cellular source of IL-17 in the small intestine [116]. Further, IL-6 can be critical trigger of IL-17 production, suggesting that the IL-33/IL-6/IL-17 axis plays a potential role in tumor biology [117]. It is well known that IL-33 is another pro-inflammatory cytokine with strong pro-angiogenic capacity (Figure 2). Similar to IL-17, IL-33 promotes the production of different pro-angiogenic factors, including VEGF and IL-8 [118]. It appears that IL-33 increases endothelial cell proliferation and vascular permeability [119]. Milosavljevic et al. [120] have found significantly higher expression of IL-33, IL-33 receptor, and VEGF in breast cancer. IL-33 and IL-33R expression correlated with VEGF expression in tumor tissue. VEGF expression positively correlated with MVD implicating that IL-33/IL-33R pathway is involved in breast cancer growth [120]. Further, tumor-derived IL-33 induces the recruitment of CD11b + Gr1+ and CD11b + F4/80+ myeloid cells to the tumor microenvironment further contributing to angiogenesis
5. Galectin-3 and IL-17 in anti-angiogenic tumor therapy
Angiogenesis is complex and dynamic process in which more actors take part. To date, several anti-angiogenic agents, mainly acting
MCP is specifically inhibitor of Galectin-3, which significant decreases the MVD, suggesting that targeting Galectin-3 may open novel perspectives to interfere with tumor angiogenesis [67]. On the other hand, anti-angiogenic treatments have therapeutic limitations including varying degrees of response and resistance due to VEGF-independent mechanisms. Thus, VEGF blockade creates hypoxic conditions in the tumor, which in turn causes increased invasion and poorer survival by inducting of HIF-1α-dependent c-Met overexpression [126]. In hypoxic areas, tumor cells also survive oxygen-depleted environment by upregulating Galectin-3 expression, which may in turn increase tumor aggressiveness [127]. The simultaneous blockade of VEGF and Galectin-3 could be providing a more potent antitumor effect, which is mediated by, among others, anti-angiogenic mechanisms.
Finally, due to the fact that multiple actors are involved in tumor angiogenesis, Galectin-3 and IL-17 targeting is likely to improve the efficacy of current anti-angiogenic tumor therapy.
Acknowledgments
This work was supported by a grant from the Ministry of Education, Science and Technological Development, Serbia (ON175069 and ON175071), a bilateral project with People’s Republic of China (06/2018) and by the Faculty of Medical Sciences of the University of Kragujevac, Serbia (JP16/19).
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