Open access peer-reviewed chapter

Modulators of Tumor Angiogenesis: Insights into the Role of Galectin-3 and IL-17 Signaling

Written By

Gordana D. Radosavljevic, Jelena Pantic, Bojana Simovic Markovic and Nebojsa Arsenijevic

Submitted: 25 January 2022 Reviewed: 27 January 2022 Published: 29 April 2022

DOI: 10.5772/intechopen.102893

From the Edited Volume

Tumor Angiogenesis and Modulators

Edited by Ke Xu

Chapter metrics overview

131 Chapter Downloads

View Full Metrics


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.


  • 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 via induction of pro-angiogenic factors such as VEGF. The better understanding of Galectin-3 and IL-17 in tumor biology will undoubtedly contribute to controlling tumor progression. Namely, we will review the role of these two molecules in tumor angiogenesis and highlight the other mechanisms involved in the acceleration of tumor growth and metastases.


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 via activation of different signaling pathways and/or polarization of macrophages toward pro-tumorigenic TAM2 phenotype. Galectin-3 affects the production of pro-inflammatory cytokines implicated in tumor promotion. Within the complex cytokine network in tumor microenvironment, IL-17 is recognized as one of the critical stimulators of the production of pro-angiogenic mediators, including VEGF. IL-17 mediates the recruitment of TAN2 thus augmenting angiogenic factors release. IL-23 and IL-33 seem to be significant co-workers in triggering angiogenic cascade. Both IL-17 and IL-33 induce recruitment of pro-angiogenic MDSC, while IL-23 further promotes function, survival, and expansions of Th17 lymphocytes, and subsequent IL-17 production. The activation, proliferation, and migration of endothelial cells, as well as sprouting and tube formation, precede the formation of new blood vessels critical for tumor progression. CAF-cancer-associated fibroblast; TAM-tumor-associated macrophage; TAN-tumor-associated neutrophil; MDSC-myeloid-derived suppressor cell; ECM-extracellular matrix.

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 in vitro and in vivo experiments, IL-17 signaling was shown to be “malevolent player” that promotes tumorigenesis and tumor progression, in many ways. In general, IL-17 exerts pro-tumor properties by direct influence on the tumor cells via triggering malignant transformation and tumor growth [55, 56] and/or indirectly by controlling chronic inflammatory and immunosuppressive tumor microenvironment, as well as angiogenesis [40, 57]. The IL-17/IL-17R axis upregulates phosphorylated ERK1/2 in breast cancer cells lines thereby promoting their proliferation, migration, and invasion [58]. Also, IL-17 can indirectly support the cell proliferation and tumor growth by shaping of tumor microenvironment through the production of chemokines and cytokines [59]. IL-17 was shown to be able to promote hepatocellular carcinoma invasion and migration by upregulation of matrix metalloproteases, MMP-2, and MMP-9, via NF-κB signaling [60]. IL-17 promotes STAT3 activity in both tumor and stromal cells, leading to upregulation of anti-apoptotic Bcl-2 and Bcl-XL in an IL-6-dependent manner [61]. This may reflect the fact that IL-17 present in the tumor microenvironment may be an important survival factor and reason for tumor chemoresistance. Accordingly, IL-17 promotes resistance of breast cancer cells to chemotherapeutic docetaxel via activation of ERK1/2 pathway [58]. Based on these findings, it can be speculated that IL-17 contributes to development of chemoresistance in variety tumor cells via activation of prosurvival and/or proliferative signaling. Recent evidence suggests that IL-17 links inflammation to tumor progression. Indeed, long-term IL-17 activity leads to pro-tumor microenvironment by inducing the secretion of inflammatory mediators and reshaping the phenotype of stromal cells [62]. Additionally, IL-17 stimulates the chemokine and VEGF expression that favor the recruitment of specific subsets of immune cells to the sites of inflammation and angiogenesis, respectively [63]. This IL-17-mediated maintenance of inflammatory environment results in the stimulation of tumor growth and metastasis via subsequent expression of anti-apoptotic molecules and increased tumor cell survival [64]. Ironically, Wang et al. [57] illustrated that IL-17, as pro-inflammatory cytokine, contributes to immune paralysis in the tumor microenvironment. Namely, IL-17 increases the expression of programmed death-ligand 1 (PD-L1) inhibitor on MSCs that shape the immunosuppressive environment and facilitate tumor progression. Further, chemokines (e.g., CXCL1 and CXCL5) stimulate the recruitment of MDSCs in IL-17-depandent manner to establish a proangiogenic and immunosuppressive tumor microenvironment [62]. Alongside its pro-tumorigenic functions, IL-17 may act as a tumor regressor. The protective role of IL-17 in tumor relies on its property to induce the vigorous immune responses to attain tumor regression. In fact, it has been demonstrated that effective antitumor immune response is mediated by Th17 lymphocytes and highly depends on IFN-γ [65]. Further, IL-17 enhances the CTLs-mediated immune response directed against hematopoietic tumors by induction of IL-6 and IL-12 production [40]. Therefore, IL-17 is multifunctional cytokine with divergent actions on tumor that are highly context-dependent. It seems that epigenetic and transcriptional modifications as well as certain cytokine milieu in the tumor microenvironment specific to each tumor type and stage may account for the functional plasticity of IL-17 making difficult to predict its role. Finally, IL-17 brings different net outcome in a complex disease such as tumor.


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 in vivo. The direct binding of Galectin-3 for endothelial cell surface appeared to be carbohydrate recognition-dependent event as it may be inhibited by disaccharide lactose and modified citrus pectin (MCP) [19, 67, 68].

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 via CRD thus promoting its clustering and subsequent activation of focal adhesion kinase (FAK) in ECs [78]. FAK is a principal regulator of endothelial cell migration, proliferation, and survival, which participates in signal transduction triggered by integrins and growth factor receptors such as VEGFRs [79]. The expression of VEGFR-2, a major mediator of VEGF effects on ECs, is tightly regulated by FAK activation, its translocation to the nucleus, and subsequent regulation of VEGFR-2 gene transcription [79]. Given its carbohydrate-binding properties, Galectin-3 engages different N-glycosylated tyrosine kinase receptors including VEGFR-2 or FGF receptor-1 (FGFR-1) [80, 81]. It has been documented that Galectin-3 induces VEGFR-2 signaling during angiogenesis through modulation of expression and clustering of receptor on the ECs thus enabling its higher availability to VEGF [81]. However, the recent study has revealed that Galectin-3 amplifies the activation of VEGFR-2 and its downstream signaling only in the presence of VEGF [82]. Moreover, Galectin-3 is not necessary for VEGF-induced activation of VEGFR-2, nor it can activate the receptor in the absence of VEGF [82].

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 via interfering with the responses of macrophages to the complex two-way VEGF and TGFβ-1 signaling pathways [91].

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 via STAT3 signaling [61, 100]. IL-17 exerts synergistic effects with TNF-α by enhancing the secretion of potent angiogenic factors by stromal fibroblasts [94], which in turn triggers the angiogenic program in ECs and stimulates the new blood vessel development [95]. The inhibition of IL-17 suppresses VEGF expression in tumor tissue and decreases intratumoral MVD, which confirms important role of IL-17 in angiogenesis [101].

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 via different mechanisms. Mostly, MDSCs stimulate angiogenesis by secreting numerous growth factors including VEGF, bFGF, and PDGF. They also remodel ECM components via MMPs production and reprogramming of other cells to tumor-promoting phenotype that are source of many angiogenesis activators [110].

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 via different mechanisms [121]. IL-33/ST2 axis rapidly increased NO production through TRAF6-mediated activation of PI3K, AKT, and NO synthase in the ECs [119]. Also, AKT signaling in the ECs is transiently regulated by angiogenic factors such as VEGF and angiopoietin-1 [122]. Taken together, the better understanding of cytokine-regulated angiogenesis, notably by IL-17, is of great importance for the rational development of new tumor therapeutic strategies.


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 via targeting VEGF and its receptor, have been in clinical use. It seems that the blockade of pro-angiogenic Galectin-3 and IL-17 might be the potential strategy to open opportunities for additional tumor immunotherapy, in particular in tumors that overexpress Galectin-3 and IL-17. It has been shown that IL-17 signaling pathways, notably, IL-17-mediated paracrine network in the tumor microenvironment, mediate tumor refractoriness to the anti-angiogenic effects of VEGF blockade [123, 124]. IL-17 induces expression of numerous cytokine, most notably, G-CSF that is essential for the development and recruitment of CD11b + Gr1+ MDSCs [97, 124] to the tumor microenvironment in which these “angiocompetent cells” probably take part in both VEGF-dependent and VEGF-independent angiogenesis [125]. Taken together, these data suggest that the inhibition of IL-17 signaling may render tumor sensitive to VEGF-targeting therapy and/or reduce the VEGF-independent tumor angiogenesis.

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.



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).


  1. 1. Folkman J. Tumor angiogenesis: Therapeutic implications. The New England Journal of Medicine. 1971;285:1182-1186. DOI: 10.1056/NEJM197111182852108
  2. 2. Nejad AE, Najafgholian S, Rostami A, Sistani A, Shojaeifar S, Esparvarinha M, et al. The role of hypoxia in the tumor microenvironment and development of cancer stem cell: A novel approach to developing treatment. Cancer Cell International. 2021;21:62. DOI: 10.1186/s12935-020-01719-5
  3. 3. Lee SH, Jeong D, Han Y-S, Baek MJ. Pivotal role of vascular endothelial growth factor pathway in tumor angiogenesis. Annals of Surgical Treatment and Research. 2015l;89:1-8. DOI: 10.4174/astr.2015.89.1.1
  4. 4. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in Cancer. Vascular Health and Risk Management. 2006;2:213-219. DOI: 10.2147/vhrm.2006.2.3.213
  5. 5. Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Experimental Cell Research. 2006;3125:549-560. DOI: 10.1016/j.yexcr.2005.11.012
  6. 6. Gee E, Milkiewicz M, Haas TL. p38 MAPK is activated by vascular endothelial growth factor receptor 2 and is essential for shear stress-induced angiogenesis. Journal of Cellular Physiology. 2010;222:120-126. DOI: 10.1002/jcp.21924
  7. 7. Yang G-L, Li L-Y. Counterbalance: Modulation of VEGF/VEGFR activities by TNFSF15. Signal Transduction and Targeted Therapy. 2018;3:21. DOI: 10.1038/s41392-018-0023-8
  8. 8. Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. The American Journal of Pathology. 1995;146:1029-1039
  9. 9. Meadows KN, Bryant P, Pumiglia K. Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. The Journal of Biological Chemistry. 2001;276:49289-49298. DOI: 10.1074/jbc.M108069200
  10. 10. Gerber HP, Dixit V, Ferrara N. Vascular endothelial growth factor induces expression of the antiapoptotic proteins Bcl-2 and A1 in vascular endothelial cells. Journal of Biological Chemistry. 1998;273:13313-13316. DOI: 10.1074/jbc.273.21.13313
  11. 11. Rafii S, Lyden D, Benezra R, Hattori K, Heissig B. Vascular and haematopoietic stem cells: Novel targets for anti-angiogenesis therapy? Nature Reviews. Cancer. 2002;2:826-835. DOI: 10.1038/nrc925
  12. 12. Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Advances in Cancer Research. 2009;102:19-65. DOI: 10.1016/S0065-230X(09)02002-8
  13. 13. Jiang X, Wang J, Deng X, Xiong F, Zhang S, Gong Z, et al. The role of microenvironment in tumor angiogenesis. Journal of Experimental & Clinical Cancer Research. 2020;39:204. DOI: 10.1186/s13046-020-01709-5
  14. 14. Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: Progress, opportunities, and challenges. Annual Review of Physiology. 2019;81:505-534. DOI: 10.1146/annurev-physiol-020518-114700
  15. 15. Wei F, Wang D, Wei J, Tang N, Tang L, Xiong F, et al. Metabolic crosstalk in the tumor microenvironment regulates antitumor immunosuppression and immunotherapy resisitance. Cellular and Molecular Life Sciences. 2020;8:284. DOI: 10.1007/s00018-020-03581-0
  16. 16. Radosavljevic G, Volarevic V, Jovanovic I, Milovanovic M, Pejnovic N, Arsenijevic N, et al. The roles of Galectin-3 in autoimmunity and tumor progression. Immunologic Research. 2012;52:100-110. DOI: 10.1007/s12026-012-8286-6
  17. 17. Radosavljevic GD, Pantic J, Jovanovic I, Lukic ML, Arsenijevic N. The two faces of Galectin-3: Roles in various pathological conditions. Serbian Journal of Experimental and Clinical Research. 2016;17:187-198. DOI: 10.1515/SJECR-2016-0011
  18. 18. Capone E, Iacobelli S, Sala G. Role of galectin 3 binding protein in cancer progression: A potential novel therapeutic target. Journal of Translational Medicine. 2021;19:405. DOI: 10.1186/s12967-021-03085-w
  19. 19. Nangia Makker P, Honjo Y, Sarvis R, Akahani S, Hogan V, Pienta KJ, et al. Galectin 3 induces endothelial cell morphogenesis and angiogenesis. The American Journal of Pathology. 2000;156:899-909. DOI: 10.1016/S0002-9440(10)64959-0
  20. 20. Henderson NC, Mackinnon AC, Farnworth SL, Poirier F, Russo FP, Iredale JP, et al. Galectin 3 regulates myofibroblast activation and hepatic fibrosis. Proceedings of the National Academy of Sciences of the United States of America. 2006;103:5060-5065. DOI: 10.1073/pnas.0511167103
  21. 21. Sioud M, Mobergslien A, Boudabous A, Fløisand Y. Evidence for the involvement of galectin 3 in mesenchymal stem cell suppression of allogeneic T cell proliferation. Scandinavian Journal of Immunology. 2010;71:267-274. DOI: 10.1111/j.1365-3083.2010.02378.x
  22. 22. Furuhata S, Ando K, Oki M, Aoki K, Ohnishi S, Aoyagi K, et al. Gene expression profiles of endothelial progenitor cells by oligonucleotide microarray analysis. Molecular and Cellular Biochemistry. 2007;298:125-138. DOI: 10.1007/s11010-006-9359-4
  23. 23. Glinskii OV, Turk JR, Pienta KJ, Huxley VH, Glinsky VV. Evidence of porcine and human endothelium activation by cancer-associated carbohydrates expressed on glycoproteins and tumour cells. The Journal of Physiology. 2004;554:89-99. DOI: 10.1113/jphysiol.2003.054783
  24. 24. Gil CD, La M, Perretti M, Oliani SM. Interaction of human neutrophils with endothelial cells regulates the expression of endogenous proteins annexin 1, galectin-1 and galectin-3. Cell Biology International. 2006;30:338-344. DOI: 10.1016/j.cellbi.2005.12.010
  25. 25. Rao SP, Wang Z, Zuberi RI, Sikora L, Bahaie NS, Zuraw BL, et al. Galectin-3 functions as an adhesion molecule to support eosinophil rolling and adhesion under conditions of flow. Journal of Immunology. 2007;179:7800-7807. DOI: 10.4049/jimmunol.179.11
  26. 26. Annese T, Tamma R, Ruggieri S, Ribatti D. Erythropoietin in tumor angiogenesis. Experimental Cell Research. 2019;374:266-273. DOI: 10.1016/j.yexcr.2018.12.013
  27. 27. Ruvolo PP. Galectin 3 as a guardian of the tumor microenvironment. Biochimica et Biophysica Acta. 2016;1863:427-437. DOI: 10.1016/j.bbamcr.2015.08.008
  28. 28. Ahmed H, AlSadek DMM. Galectin-3 as a potential target to prevent Cancer metastasis. Clinical Medicine Insights: Oncology. 2015;9:113-121. DOI: 10.4137/CMO.S29462
  29. 29. Farhad M, Rolig AS, Redmonda WL. The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. OncoImmunology. 2018;7:e1434467. DOI: 10.1080/2162402X.2018.1434467
  30. 30. Wang L, Li Y-S, Yu L-G, Zhang X-K, Zhao L, Gong F-L, et al. Galectin-3 expression and secretion by tumor-associated macrophages in hypoxia promotes breast cancer progression. Biochemical Pharmacology. 2020;178:114113. DOI: 10.1016/j.bcp.2020.114113
  31. 31. Çakır Y, Talu CK, Mermut Ö, Trabulus DC, Arslan E. The expression of Galectin-3 in tumor and Cancer-associated fibroblasts in invasive micropapillary breast carcinomas: Relationship with Clinicopathologic parameters. European Journal Of Breast Health. 2021;17:341-351. DOI: 10.4274/ejbh.galenos.2021.2021-2-8
  32. 32. Escrevente C, Grammel N, Kandzia S, Zeiser J, Tranfield EM, Conradt HS, et al. Sialoglycoproteins and N-glycans from secreted exosomes of ovarian carcinoma cells. PLoS One. 2013;8:e78631. DOI: 10.1371/journal.pone.0078631
  33. 33. Dange MC, Srinivasan N, More SK, Bane SM, Upadhya A, Ingle AD, et al. Galectin-3 expressed on different lung compartments promotes organ specific metastasis by facilitating arrest, extravasation and organ colonization via high affinity ligands on melanoma cells. Clinical & Experimental Metastasis. 2014;31:661-673. DOI: 10.1007/s10585-014-9657-2
  34. 34. Radosavljevic G, Jovanovic I, Majstorovic M, Mitrovic M, Juranic Lisnic V, Arsenijevic N, et al. Deletion of Galectin-3 in the host attenuates metastasis of murine melanoma by modulating tumor adhesion and NK cell activity. Clinical & Experimental Metastasis. 2011;28:451-462. DOI: 10.1007/s10585-011-9383-y
  35. 35. Aguilar-Cazares D, Chavez-Dominguez R, Carlos-Reyes A, Lopez-Camarillo C, Hernadez de la Cruz ON, Lopez-Gonzalez JS. Contribution of angiogenesis to inflammation and Cancer. Frontiers in Oncology. 2019;9:1399. DOI: 10.3389/fonc.2019.01399
  36. 36. Jia W, Kidoya H, Yamakawa D, Naito H, Takakura N. Galectin-3 accelerates M2 macrophage infiltration and angiogenesis in tumors. The American Journal of Pathology. 2013;182:1821-1831. DOI: 10.1016/j.ajpath.2013.01.017
  37. 37. Chen C, Duckworth CA, Zhao Q, Pritchard DM, Rhodes JM, Yu L-G. Increased circulation of galectin-3 in cancer induces secretion of metastasis-promoting cytokines from blood vascular endothelium. Clinical Cancer Research. 2013;19:1693-1704. DOI: 10.1158/1078-0432.CCR-12-2940
  38. 38. Goldberg JE, Schwertfeger KL. Proinflammatory cytokines in breast cancer: Mechanisms of action and potential targets for therapeutics. Current Drug Targets. 2010;11:1133-1146. DOI: 10.2174/138945010792006799
  39. 39. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA. Chronic inflammation and cytokines in the tumor microenvironment. Journal of Immunology Research. 2014;2014:149185. DOI: 10.1155/2014/149185
  40. 40. Murugaiyan G, Saha B. Protumor vs antitumor functions of IL-17. Journal of Immunology. 2009;183:4169-4175. DOI: 10.4049/jimmunol.0901017
  41. 41. Shimura T, Shibata M, Gonda K, Nakajima T, Chida S, Noda M, et al. Association between circulating galectin-3 levels and the immunological, inflammatory and nutritional parameters in patients with colorectal cancer. Biomedical Reports. 2016;5:203-207. DOI: 10.3892/br.2016.696
  42. 42. Yun G, Huang M, Yao Y-M. Biology of Interleukin-17 and its pathophysiological significance in Sepsis. Frontiers in Immunology. 2020;11:1558. DOI: 10.3389/fimmu.2020.01558
  43. 43. Du J-W, Xu K-Y, Fang L-Y, Qi X-L. Interleukin-17, produced by lymphocytes, promotes tumor growth and angiogenesis in a mouse model of breast cancer. Molecular Medicine Reports. 2012;6:1099-1102. DOI: 10.3892/mmr.2012.1036
  44. 44. Su X, Ye J, Hsueh EC, Zhang Y, Hoft DF, Peng G. Tumor microenvironments direct the recruitment and expansion of human Th17 cells. Journal of Immunology. 2010;184:1630-1641. DOI: 10.4049/jimmunol.0902813
  45. 45. Chen C, Gao F-H. Th17 cells paradoxical roles in melanoma and potential application in immunotherapy. Frontiers in Immunology. 2019;10:187. DOI: 10.3389/fimmu.2019.00187
  46. 46. Dang EV, Barbi J, Yang H-Y, Jinasena D, Yu H, Zheng Y, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772-784. DOI: 10.1016/j.cell.2011.07.033
  47. 47. Sharma MD, Hou D-Y, Liu Y, Koni PA, Metz R, Chandler P, et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood. 2009;113:6102-6111. DOI: 10.1182/blood-2008-12-1953
  48. 48. Li J, Huang Z-F, Xiong G, Mo H-Y, Qiu F, Mai H-Q, et al. Distribution, characterization, and induction of CD8+ regulatory T cells and IL-17-producing CD8+ T cells in nasopharyngeal carcinoma. Journal of Translational Medicine. 2011;9:189. DOI: 10.1186/1479-5876-9-189
  49. 49. Zhuang Y, Peng L-S, Zhao Y-L, Shi Y, Mao X-H, Chen W, et al. CD8(+) T cells that produce interleukin-17 regulate myeloid-derived suppressor cells and are associated with survival time of patients with gastric cancer. Gastroenterology. 2012;143:951-62.e8. DOI: 10.1053/j.gastro.2012.06.010
  50. 50. Meng S, Li L, Zhou M, Jiang W, Niu H, Yang K. Distribution and prognostic value of tumor-infiltrating T cells in breast cancer. Molecular Medicine Reports. 2018;18:4247-4258. DOI: 10.3892/mmr.2018.9460
  51. 51. Patin EC, Soulard D, Fleury S, Hassane M, Dombrowicz D, Faveeuw C, et al. Type I IFN receptor Signaling controls IL7-dependent accumulation and activity of Protumoral IL17A-producing γδT cells in breast Cancer. Cancer Research. 2018;78:195-204. DOI: 10.1158/0008-5472.CAN-17-1416
  52. 52. Kuen D-S, Kim B-S, Chung Y. IL-17-producing cells in tumor immunity: Friends or foes? Immune Network. 2020;20:e6. DOI: 10.4110/in.2020.20.e6
  53. 53. Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cellular Signalling. 2011;23:1069-1075. DOI: 10.1016/j.cellsig.2010.11.022
  54. 54. Jiang Y-X, Li P-A, Yang S-W, Hao Y-X, Yu P-W. Increased chemokine receptor IL-17RA expression is associated with poor survival in gastric cancer patients. International Journal of Clinical and Experimental Pathology. 2015;8:7002-7008
  55. 55. Kim G, Khanal P, Lim SC, Yun HJ, Ahn SG, Ki SH, et al. Interleukin-17 induces AP-1 activity and cellular transformation via upregulation of tumor progression locus 2 activity. Carcinogenesis. 2013;34:341-350. DOI: 10.1093/carcin/bgs342
  56. 56. Nam JS, Terabe M, Kang MJ, Chae H, Voong N, Yang YA, et al. Transforming growth factor β subverts the immune system into directly promoting tumor growth through interleukin-17. Cancer Research. 2008;68:3915-3923. DOI: 10.1158/0008-5472.CAN-08-0206
  57. 57. Wang S, Wang G, Zhang L, Li F, Liu K, Wang Y, et al. Interleukin 17 promotes nitric oxide dependent expression of PD L1 in mesenchymal stem cells. Cell & Bioscience. 2020;10:73. DOI: 10.1186/s13578-020-00431-1
  58. 58. Cochaud S, Giustiniani J, Thomas C, Laprevotte E, Garbar C, Savoye A-M, et al. IL-17A is produced by breast cancer TILs and promotes chemoresistance and proliferation through ERK1/2. Scientific Reports. 2013;3:3456. DOI: 10.1038/srep03456
  59. 59. Vitiello GA, Miller G. Targeting the interleukin-17 immune axis for cancer immunotherapy. The Journal of Experimental Medicine. 2020;217:e20190456. DOI: 10.1084/jem.20190456
  60. 60. Li J, Lau GK, Chen L, Dong SS, Lan HY, Huang XR, et al. Interleukin 17A promotes hepatocellular carcinoma metastasis via NF-kB induced matrix metalloproteinases 2 and 9 expression. PLoS One. 2011;6:e21816. DOI: 10.1371/journal.pone.0021816
  61. 61. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. The Journal of Experimental Medicine. 2009;206:1457-1464. DOI: 10.1084/jem.20090207
  62. 62. Zhao J, Chen X, Herjan T, Li X. The role of interleukin-17 in tumor development and progression. The Journal of Experimental Medicine. 2020;217:e20190297. DOI: 10.1084/jem.20190297
  63. 63. Welte T, Zhang XH-F. Interleukin-17 could promote breast Cancer progression at several stages of the disease. Mediators of Inflammation. 2015;2015:804347. DOI: 10.1155/2015/804347
  64. 64. Yang B, Kang H, Fung A, Zhao H, Wang T, Ma D. The role of interleukin 17 in tumour proliferation, angiogenesis, and metastasis. Mediators of Inflammation. 2014;2014:623759. DOI: 10.1155/2014/623759
  65. 65. Muranski P, Boni A, Antony PA, Cassard L, Irvine KR, Kaiser A, et al. Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood. 2008;112:362-373. DOI: 10.1182/blood-2007-11-120998
  66. 66. Thijssen VL. Galectins in endothelial cell biology and angiogenesis: The basics. Biomolecules. 2021;11:1386. DOI: 10.3390/biom11091386
  67. 67. Nangia-Makker P, Hogan V, Honjo Y, Baccarini S, Tait L, Bresalier R, et al. Inhibition of human cancer cell growth and metastasis in nude mice by oral intake of modified citrus pectin. Journal of the National Cancer Institute. 2002;94:1854-1862. DOI: 10.1093/jnci/94.24.1854
  68. 68. Funasaka T, Raz A, Nangia-Makker P. Galectin-3 in angiogenesis and metastasis. Glycobiology. 2014;24:886-891. DOI: 10.1093/glycob/cwu086
  69. 69. Fukushi J, Makagiansar IT, Stallcup WB. NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of Galectin-3 and α3β1 integrin. Molecular Biology of the Cell. 2004;15:3580-3590. DOI: 10.1091/mbc.e04-03-0236
  70. 70. Sedlář A, Trávníčková M, Bojarová P, Vlachová M, Slámová K, Křen V, et al. Interaction between Galectin-3 and Integrins mediates cell-matrix adhesion in endothelial cells and mesenchymal stem cells. International Journal of Molecular Sciences. 2021;22:5144. DOI: 10.3390/ijms22105144
  71. 71. Zhang Z, Zheng Y, Wang H, Zhou Y, Tai G. CD146 interacts with galectin-3 to mediate endothelial cell migration. FEBS Letters. 2018;592:1817-1828. DOI: 10.1002/1873-3468.13083
  72. 72. Jiang T, Zhuang J, Duan H, Luo Y, Zeng Q, Fan K, et al. CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood. 2012;120:2330-2339. DOI: 10.1182/blood-2012-01-406108
  73. 73. Colomb F, Wang W, Simpson D, Zafar M, Beynon R, Rhodes JM, et al. Galectin-3 interacts with the cell-surface glycoprotein CD146 (MCAM, MUC18) and induces secretion of metastasis-promoting cytokines from vascular endothelial cells. Journal of Biological Chemistry. 2017;292:8381-8389. DOI: 10.1074/jbc.M117.783431
  74. 74. Gallardo-Vara E, Ruiz-Llorente L, Casado-Vela J, Ruiz-Rodríguez MJ, López-Andrés N, Pattnaik AK, et al. Endoglin protein Interactome profiling identifies TRIM21 and Galectin-3 as new binding partners. Cell. 2019;8:1082. DOI: 10.3390/cells8091082
  75. 75. Bernabeu C, Lopez-Novoa JM, Quintanilla M. The emerging role of TGF-beta superfamily coreceptors in cancer. Biochimica et Biophysica Acta. 2009;1792:954-973. DOI: 10.1016/j.bbadis.2009.07.003
  76. 76. Nangia-Makker P, Raz T, Tait L, Hogan V, Fridman R, Raz A. Galectin-3 cleavage: A novel surrogate marker for matrix metalloproteinase activity in growing breast cancers. Cancer Research. 2007;67:11760-11768. DOI: 10.1158/0008-5472.CAN-07-323
  77. 77. Nangia-Makker P, Wang Y, Raz T, Tait L, Balan V, Hogan V, et al. Cleavage of galectin-3 by matrix metalloproteases induces angiogenesis in breast cancer. International Journal of Cancer. 2010;127:2530-2541. DOI: 10.1002/ijc.25254
  78. 78. Markowska AI, Liu FT, Panjwani N. Galectin-3 is an important mediator of VEGF- and bFGF-mediated angiogenic response. The Journal of Experimental Medicine. 2010;207:1981-1993. DOI: 10.1084/jem.20090121
  79. 79. Sun S, Wu HJ, Guan JL. Nuclear FAK and its kinase activity regulate VEGFR2 transcription in angiogenesis of adult mice. Scientific Reports. 2018;8:2550. DOI: 10.1038/s41598-018-20930-z
  80. 80. Markowska AI, Jefferies KC, Panjwani N. Galectin-3 protein modulates cell surface expression and activation of vascular endothelial growth factor receptor 2 in human endothelial cells. The Journal of Biological Chemistry. 2011;286:29913-29921. DOI: 10.1074/jbc.M111.226423
  81. 81. Kucińska M, Porębska N, Lampart A, Latko M, Knapik A, Zakrzewska M, et al. Differential regulation of fibroblast growth factor receptor 1 trafficking and function by extracellular galectins. Cell Communication and Signaling: CCS. 2019;17:65. DOI: 10.1186/s12964-019-0371-1
  82. 82. Cano I, Hu Z, AbuSamra DB, Saint-Geniez M, Ng YSE, Argüeso P, et al. Galectin-3 enhances vascular endothelial growth factor-a receptor 2 activity in the presence of vascular endothelial growth factor. Frontiers in Cell and Development Biology. 2021;9:734346. DOI: 10.3389/fcell.2021.734346
  83. 83. Dos Santos SN, Sheldon H, Pereira JX, Paluch C, Bridges EM, El-Cheikh MC, et al. Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/notch activation. Oncotarget. 2017;8:49484-49501. DOI: 10.18632/oncotarget.17718
  84. 84. Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009;137:1124-1135. DOI: 10.1016/j.cell.2009.03.025
  85. 85. Song M, Pan Q, Yang J, He J, Zeng J, Cheng S, et al. Galectin-3 favours tumour metastasis via the activation of β-catenin signalling in hepatocellular carcinoma. British Journal of Cancer. 2020;123:1521-1534. DOI: 10.1038/s41416-020-1022-4
  86. 86. Song S, Mazurek N, Liu C, Sun Y, Ding QQ, Liu K, et al. Galectin-3 mediates nuclear beta-catenin accumulation and Wnt signaling in human colon cancer cells by regulation of glycogen synthase kinase-3beta activity. Cancer Research. 2009;69:1343-1349. DOI: 10.1158/0008-5472.CAN-08-4153
  87. 87. Gurung S, Perocheau D, Touramanidou L, Baruteau J. The exosome journey: From biogenesis to uptake and intracellular signaling. Cell Communication and Signaling: CCS. 2021;19:47. DOI: 10.1186/s12964-021-00730-1
  88. 88. Piccolo E, Tinari N, Semeraro D, Traini S, Fichera I, Cumashi A, et al. LGALS3BP, lectin galactoside-binding soluble 3 binding protein, induces vascular endothelial growth factor in human breast cancer cells and promotes angiogenesis. Journal of Molecular Medicine (Berlin, Germany). 2013;91:83-94. DOI: 10.1007/s00109-012-0936-6
  89. 89. Song Y, Wang M, Tong H, Tan Y, Hu X, Wang K, et al. Plasma exosomes from endometrial cancer patients contain LGALS3BP to promote endometrial cancer progression. Oncogene. 2021;40:633-646. DOI: 10.1038/s41388-020-01555-x
  90. 90. Fu LQ, Du WL, Cai MH, Yao JY, Zhao YY, Mou XZ. The roles of tumor-associated macrophages in tumor angiogenesis and metastasis. Cellular Immunology. 2020;353:104119. DOI: 10.1016/j.cellimm.2020.104119
  91. 91. Machado CM, Andrade LN, Teixeira VR, Costa FF, Melo CM, dos Santos SN, et al. Galectin-3 disruption impaired tumoral angiogenesis by reducing VEGF secretion from TGFb1-induced macrophages. Cancer Medicine. 2014;3:201-214. DOI: 10.1002/cam4.173
  92. 92. Liu J, Duan Y, Cheng X, Chen X, Xie W, Long H, et al. IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma. Biochemical and Biophysical Research Communications. 2011;407:348-354. DOI: 10.1016/j.bbrc.2011.03.021
  93. 93. Zhang JP, Yan J, Xu J, Pang XH, Chen MS, Li L, et al. Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. Journal of Hepatology. 2009;50:980-989. DOI: 10.1016/j.jhep.2008.12.033
  94. 94. Numasaki M, Lotze MT, Sasaki H. Interleukin-17 augments tumor necrosis factor-alpha-induced elaboration of proangiogenic factors from fibroblasts. Immunology Letters. 2004;93:39-43. DOI: 10.1016/j.imlet.2004.01.014
  95. 95. Takahashi H, Numasaki M, Lotze MT, Sasaki H. Interleukin-17 enhances bFGF-, HGF- and VEGF-induced growth of vascular endothelial cells. Immunology Letters. 2005;98:189-193. DOI: 10.1016/j.imlet.2004.11.012
  96. 96. Wu X, Yang T, Liu X, Nian Guo J, Xie T, Ding Y, et al. IL-17 promotes tumor angiogenesis through Stat3 pathway mediated upregulation of VEGF in gastric cancer. Tumour Biology. 2016;37:5493-5501. DOI: 10.1007/s13277-015-4372-4
  97. 97. He D, Li H, Yusuf N, Elmets CA, Li J, Mountz JD, et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. Journal of Immunology. 2010;184:2281-2288. DOI: 10.4049/jimmunol.0902574
  98. 98. Yuan S, Zhang S, Zhuang Y, Zhang H, Bai J, Hou Q. Interleukin-17 stimulates STAT3-mediated endothelial cell activation for neutrophil recruitment. Cellular Physiology and Biochemistry. 2015;36(6):2340-2356. DOI: 10.1159/000430197
  99. 99. Pan B, Shen J, Cao J, Zhou Y, Shang L, Jin S, et al. Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. Scientific Reports. 2020;10:8808. DOI: 10.1038/s41598-020-65650-5
  100. 100. Levy DE, Darnell JE Jr. Stats: Transcriptional control and biological impact. Nature Reviews. Molecular Cell Biology. 2002;3:651-662. DOI: 10.1038/nrm909
  101. 101. Hayata K, Iwahashi M, Ojima T, Katsuda M, Iida T, Nakamori M, et al. Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice. PLoS One. 2013;8:e53131. DOI: 10.1371/journal.pone.0053131
  102. 102. Kehlen A, Thiele K, Riemann D, Rainov N, Langner J. Interleukin-17 stimulates the expression of IkappaB alpha mRNA and the secretion of IL-6 and IL-8 in glioblastoma cell lines. Journal of Neuroimmunology. 1999;101:1-6. DOI: 10.1016/s0165-5728(99)00111-3
  103. 103. Waugh DJJ, Wilson C. The interleukin-8 pathway in cancer. Clinical Cancer Research. 2008;14:6735-6741. DOI: 10.1158/1078-0432.CCR-07-4843
  104. 104. Ardi VC, Kupriyanova TA, Deryugina EI, Quigley JP. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proceedings of the National Academy of Sciences of the United States of America. 2007;104:20262-20267. DOI: 10.1073/pnas.0706438104
  105. 105. Su Z, Sun Y, Zhu H, Liu Y, Lin X, Shen H, et al. Th17 cell expansion in gastric cancer may contribute to cancer development and metastasis. Immunologic Research. 2014;58:118-124. DOI: 10.1007/s12026-013-8483-y
  106. 106. Numasaki M, Watanabe M, Suzuki T, Takahashi H, Nakamura A, McAllister F, et al. IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis. Journal of Immunology. 2005;175:6177-6189. DOI: 10.4049/jimmunol.175.9.6177
  107. 107. Keeley EC, Mehrad B, Strieter RM. Chemokines as mediators of tumor angiogenesis and neovascularization. Experimental Cell Research. 2011;317:685-690. DOI: 10.1016/j.yexcr.2010.10.020
  108. 108. Fridlender ZG, Sun J, Kim S, Kapoor V, Cheng G, Ling L, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. Cancer Cell. 2009;16:183-194. DOI: 10.1016/j.ccr.2009.06.017
  109. 109. Parker KH, Beury DW, Ostrand-Rosenberg S. Myeloid-derived suppressor cells: Critical cells driving immune suppression in the tumor microenvironment. Advances in Cancer Research. 2015;128:95-139. DOI: 10.1016/bs.acr.2015.04.002
  110. 110. Vetsika E-K, Koukos A, Kotsakis A. Myeloid-derived suppressor cells: Major figures that shape the immunosuppressive and Angiogenic network in Cancer. Cell. 2019;8:1647. DOI: 10.3390/cells8121647
  111. 111. Iida T, Iwahashi M, Katsuda M, Ishida K, Nakamori M, Nakamura M, et al. Tumor-infiltrating CD4+ Th17 cells produce IL-17 in tumor microenvironment and promote tumor progression in human gastric cancer. Oncology Reports. 2011;25:1271-1277. DOI: 10.3892/or.2011.1201
  112. 112. Ljujic B, Radosavljevic G, Jovanovic I, Pavlovic S, Zdravkovic N, Milovanovic M, et al. Elevated serum level of IL-23 correlates with expression of VEGF in human colorectal carcinoma. Archives of Medical Research. 2010;41:182-189. DOI: 10.1016/j.arcmed.2010.02.009
  113. 113. Radosavljevic G, Ljujic B, Jovanovic I, Srzentic Z, Pavlovic S, Zdravkovic N, et al. Interleukin-17 may be a valuable serum tumour marker in patients with colorectal carcinoma. Neoplasma. 2010;57:135-144. DOI: 10.4149/neo_2010_02_135
  114. 114. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:46146-46145. DOI: 10.1038/nature04808
  115. 115. Liang M, Liwen Z, Yun Z, Yanbo D, Jianping C. Serum levels of IL-33 and correlation with IL-4, IL-17A, and hypergammaglobulinemia in patients with autoimmune hepatitis. Mediators of Inflammation. 2018;2018:7964654. DOI: 10.1155/2018/7964654
  116. 116. Pascual-Reguant A, Bayat Sarmadi J, Baumann C, Noster R, Cirera-Salinas D, Curato C, et al. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine. Mucosal Immunology. 2017;10:1431-1442. DOI: 10.1038/mi.2017.5
  117. 117. Cui G, Yuan A, Pang Z, Zheng W, Li Z, Goll R. Contribution of IL-33 to the pathogenesis of colorectal Cancer. Frontiers in Oncology. 2018;8:561. DOI: 10.3389/fonc.2018.00561
  118. 118. Theoharides TC, Zhang B, Kempuraj D, Tagen M, Vasiadi M, Angelidou A, et al. IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proceedings of the National Academy of Sciences of the United States of America. 2010;107:4448-4453. DOI: 10.1073/pnas.1000803107
  119. 119. Choi YS, Choi HJ, Min JK, Pyun BJ, Maeng YS, Park H, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood. 2009;114:3117-3126. DOI: 10.1182/blood-2009-02-203372
  120. 120. Milosavljevic MZ, Jovanovic IP, Pejnovic NN, Mitrovic SL, Arsenijevic NN, Simovic Markovic BJ, et al. Deletion of IL-33R attenuates VEGF expression and enhances necrosis in mammary carcinoma. Oncotarget. 2016;7:18106-18115. DOI: 10.18632/oncotarget.7635
  121. 121. Zhang Y, Davis C, Shah S, Hughes D, Ryan JC, Altomare D, et al. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Molecular Carcinogenesis. 2017;56:272-287. DOI: 10.1002/mc.22491
  122. 122. Zhu WH, MacIntyre A, Nicosia RF. Regulation of angiogenesis by vascular endothelial growth factor and angiopoietin-1 in the rat aorta model: Distinct temporal patterns of intracellular signaling correlate with induction of angiogenic sprouting. The American Journal of Pathology. 2002;161:823-830. DOI: 10.1016/S0002-9440(10)64242-3
  123. 123. Chung AS, Wu X, Zhuang G, Ngu H, Kasman I, Zhang J, et al. An interleukin-17-mediated paracrine network promotes tumor resistance to anti-angiogenic therapy. Nature Medicine. 2013;19:1114-1123. DOI: 10.1038/nm.3291
  124. 124. Maniati E, Hagemann T. IL-17 mediates resistance to anti-VEGF therapy. Nature Medicine. 2013;19:1092-1094. DOI: 10.1038/nm.3333
  125. 125. Rivera LB, Bergers G. Intertwined regulation of angiogenesis and immunity by myeloid cells. Trends in Immunology. 2015;36:240-249. DOI: 10.1016/
  126. 126. Lu KV, Bergers G. Mechanisms of evasive resistance to anti-VEGF therapy in glioblastoma. CNS Oncology. 2013;2:49-65. DOI: 10.2217/cns.12.36
  127. 127. de Oliveira JT, Ribeiro C, Barros R, Gomes C, de Matos AJ, Reis CA, et al. Hypoxia up-regulates Galectin-3 in mammary tumor progression and metastasis. PLoS One. 2015;10:e0134458. DOI: 10.1371/journal.pone.0134458

Written By

Gordana D. Radosavljevic, Jelena Pantic, Bojana Simovic Markovic and Nebojsa Arsenijevic

Submitted: 25 January 2022 Reviewed: 27 January 2022 Published: 29 April 2022