Angiogenesis, also termed neovascularization, is blood vessel development from pre-existing vasculature. It is regulated by a careful balance of pro- and anti-angiogenic factors. Normal wound healing, tissue regeneration, and physiological growth are associated with angiogenesis; however, unbalanced angiogenesis is a prerequisite for solid tumor development and, therefore, an important research area [8,9]. Tumor vasculature is characterized by an abnormal basement membrane, discontinuous and irregularly shaped endothelium, and tortuous hyperpermeable blood vessels that leak nutrients to support cancer growth, development, and resistance [10]. Tumor blood vessels are disorganized and difficult to identify as arterioles, venules, or capillaries [11]. A diverse group of cells, including endothelial cells, cancer cells, cancer-associated adipocytes, fibroblasts, neutrophils, and macrophages influence tumor vasculature morphology and functionality (Figure 1) [12,13,14,15]. For example, TAMs promote angiogenesis by secreting various pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), metalloproteinases (MMPs), TGF-β, platelet-derived growth factor (PDGF), and adrenomedullin (ADM) [16]. Overall, angiogenesis is a complicated process that involves a diverse group of cells that secrete various angiogenic factors and cytokines. Here, we discuss some major cytokines that are specifically involved in angiogenesis.

The VEGF family includes VEGF-A, -B, -C, -D, and placental growth factor (PIGF). VEGF-A is known to bind VEGF receptors 1 and 2, while VEGF-B and PIGF bind VEGF receptor 1 only [17]. Under oxygen-deprived conditions, hypoxia-inducible factors (HIF-1α and HIF-2α) induce TAMs to increase VEGF-A secretion and, thus, promote angiogenesis [18]. CAFs are major stromal resident cells that secrete several aggressive angiogenic factors, including FGF2, FGF7, IL-6, and VEGF-A [19]. Several studies indicate that VEGF regulates angiogenesis in several cancer types. For example, VEGF serum levels are correlated with vascular invasion, metastases, tumor stage, and tumor grade of bladder cancer [20]. One study indicated that TAMs overexpressing VEGF-C promoted lymphovascularization in Merkel cell carcinoma [21,22]. As mentioned previously, MMPs also play a major role in driving angiogenesis and may be related to VEGF levels. Early chicken chorioallantoic membrane models and mouse models demonstrated that MMP-2 downregulation and deficiencies are associated with tumor angiogenesis [23,24]. Interestingly, MMP-9- and MT1-MMP-deficient mice present decreased angiogenesis, compared with wild type [25,26,27]. One study proposed that MMP-2 may modify VEGF expression after observing reduced VEGF expression in A549 lung cancer xenograft tissue samples from mice treated with MMP-2 siRNA [28]. Several studies demonstrate that MMPs enhance VEGF production; however, the exact mechanism is unknown [29]. In addition to angiogenesis in solid tumors, VEGF may be associated with hematological malignancies [30]. Recently, Filipiak et al. used an enzyme-linked immunosorbent assay (ELISA) to measure VEGF-A levels in 42 Hodgkin’s lymphoma patients and found that VEGF-A concentration was significantly elevated compared to healthy patient levels [31]. Another study showed that treating Raji cells with oxacetaxine and curcumin, which have antiproliferative effects on lymphoma cells, results in suppressed VEGF-A levels in exosomes derived from Raji cells, and decreases phosphorylated VEGF receptor 2 (p-VEGFR2) levels [32]. VEGF may also be used to predict the prognosis of diffuse large B cell lymphoma (DLBCL) patients. Sang et al. performed a retrospective study and discovered that upregulated VEGF was related to poor therapeutic response and survival of DLBCL patients [33]. In summary, extensive research has identified VEGF as an angiogenesis biomarker and potential therapeutic target.

A recent preclinical study showed that propofol, a common intravenous anesthetic, could inhibit VEGF/VEGFR2- and mTOR/eIF4E-mediated signaling pathways to induce anti-angiogenic activity [34]. However, the relationship between propofol and angiogenesis will require further investigation because both anti-angiogenic and pro-angiogenic effects are reported [35,36]. Anti-VEGF antibodies may target VEGF and inhibit angiogenesis. For example, humanized mAb bevacizumab targets VEGF-A isoforms and was approved in the US in 2004 to be used in combination with chemotherapy for colorectal cancer treatment. Today, it is also approved to treat ovarian, cervical, glioblastoma, and renal cancers [20]. Bevacizumab is also being tested as a potential treatment option for other cancers (Table 1). In one case study, a 21-year-old female with central nervous system (CNS) acute myeloid leukemia (AML) relapse was treated with bevacizumab and intrathecal (IT) chemotherapy. As a result, she remained in complete remission for nearly 1 year. Results suggest that bevacizumab may prove to be a good combination treatment for AML patients [37].

PIGF is a potential prognostic cancer biomarker, like other VEGF family members, and is involved in endothelial stimulation, bone marrow-derived cell activation, and angiogenesis [38]. In one study, the serum levels of PIGF from 49 clear cell ccRCC patients were tested before surgery and 3 months post-surgery. Before surgery, patients with primary metastatic ccRCC had significantly elevated PIGF levels, compared with localized, without-relapse ccRCC patients [39]. Phage-display technology identified PIGF-specific nanobodies in the nM range that demonstrate anti-angiogenic activity [40,41]. Humanized anti-PIGF antibody TB-403 was tested in patients with advanced solid tumors in phase I clinical trial and pediatric patients with relapsed or refractory medulloblastoma (NCT02748135) [42]. Results are expected to be released in 2022 [43].

Hepatocyte growth factor (HGF) is a scatter factor that promotes EMT, by activating metalloproteinases, and potently binds to heparin-binding angiogenic factor [44]. HGF is a stromal-cell-derived cytokine and the natural endogenous ligand for mesenchymal–epithelial transition (MET) receptor tyrosine kinase (RTK), which is encoded by the MET proto-oncogene on human chromosome 7 [45]. HGF/MET signaling activation drives angiogenesis, cell proliferation, and tumor aggressiveness [46]. Elevated levels are associated with poor colorectal and lung cancer survival [47,48]. Recently, Katayama et al. revealed that high HGF serum levels in muscle-invasive bladder cancer (MIBC) patients are associated with worse cancer-specific survival, recurrence-free survival, and overall survival [49]. Another study found that patients with gastric cancer have elevated plasma HGF levels, compared with patients with normal gastric mucosa or gastric ulcers [50]. Developing novel treatments targeting both HGF-dependent and HGF-independent MET activation will be important for future treatments targeting the oncogenic-driving MET pathway [51].

Interleukins are involved in multiple cancer processes, including angiogenesis. The IL-1 family comprises IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA). IL-1α and IL-1β are cancer-promoting and drive angiogenesis, tumor progression, and tumor aggressiveness [52]. CAFs and adipocytes are known to promote these processes through IL-1β secretion [53]. Early studies of B16 melanoma mouse models showed that IL-1β is required for angiogenesis via lymphotoxin and VEGF-A induction, while IL-1α promoted a similar but weaker phenotype [54,55]. Endothelial cells act as both direct and indirect targets of IL-1 signaling and produce VEGF upon activation (Figure 2). IL-1 and VEGF may synergize to enhance angiogenesis [53]. IL-1β/IL-1R1 signaling induces additional IL-1β transcription in macrophages, which promotes fibroblasts and endothelial cells to also contribute to angiogenesis [56]. Recently, Machelke et al. found that epidermal growth factor receptor (EGFR) inhibition in A549 lung cancer cells leads to reduced IL-1β-induced tissue factor (TF) expression, which normally promotes tumor progression and angiogenesis [57]. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial evaluated anti-IL-1β to treat atherosclerosis, and results indicated that treatment significantly reduced lung cancer incidence [52,58].

Other interleukins, such as IL-6 and IL-8, may also mediate angiogenesis. Early studies showed that serum IL-6 and VEGF levels are related. IL-6 may induce VEGF expression to increase vasculature [59]. IL-6 is known to transmit signals through several signaling pathways, including JAK/STAT, RAS/MAPK, PI3K/Akt, and NF-κB, to drive tumor progression [60]. IL-6 binds to the IL-6 receptor (IL-6R), which results in the release of its associated Janus kinase (JAK) to phosphorylate transcription 3 (STAT3) and initiates downstream signals to promote angiogenesis, proliferation, and prevent apoptosis [61]. Li et al. demonstrated that IL-6 increases angiogenesis via the STAT5/P-STAT5 signaling pathway and that 6-phosphofrutcto-2-kinase/fructose-2, 6-bisphosphatase 4 (PFKFB4) expression elicits IL-6 upregulation via NF-κB signaling to increase breast cancer angiogenesis [62]. Several potential treatment strategies to target IL-6 are currently undergoing investigation. Examples include (1) small molecule Madindoline A to inhibit dimerization of IL-6/IL-6R/gp130 complexes, (2) siltuximab and CNTO-136 to inhibit IL-6 activity, and (3) mAb tocilizumab to block IL-6R [61]. IL-8 is a chemokine that binds C–X–C motif chemokine receptor 1 (CXCR1) and CXCR2, which are G-protein coupled receptors displayed on granulocytes, monocytes, and endothelial cells to increase angiogenesis, recruit immunosuppressive cells to the tumor site, and worsen prognosis [63]. IL-8 was demonstrated to be the primary cytokine involved in increasing endothelial cell permeability and cell junction disruption in glioblastoma [64]. In human colorectal cancer mouse models, IL-8 induces significant increases in CD31+ peritumoral vasculature, while CXCR2 knockout results in significantly reduced tumor growth, potentially due to lack of IL-8 signaling [65]. Interestingly, gastric cancer cells treated with nicotine, an alkaloid found in tobacco, show enhanced angiogenesis and proliferation in the TME by stimulating IL-8 expression via ROS/NF-κB and ROS/MAPK (Erk1/2, p38)/AP-1 pathways [66]. Like other interleukins, IL-8 may also be targeted for cancer treatment. Recently, escin, a pentacyclic triterpenoid derived from horse chestnut, demonstrated antitumor activity against pancreatic cancer cells by influencing IL-8 expression. Results indicated that escin-treated pancreatic cancer cells had significantly reduced NF-κB activity and IL-8 and VEGF secretion, resulting in inhibited angiogenesis [67].

The angiopoietin family consists of four members that bind to Tie-2 receptors on endothelial cells [44]. Generally, Ang-1 is described as a strong Tie-2 agonist, while Ang-2 is a Tie-2 antagonist that competes with Ang-1. However, recent studies characterize Ang-2 as capable of acting as a Tie-2 agonist or antagonist [68]. In colorectal cancer, Ang-2 expression is negatively associated with patient overall survival [69]. One study demonstrated that glucocorticoid-treated colon cancer-derived myofibroblasts reduce Ang-2 levels and inhibit endothelial cell angiogenesis and cell migration [70]. Ang-4 and Ang-3, a mouse orthologue, are both Tie-2 agonists, but their effect on angiogenesis is not well characterized [71]. A recent study showed that Ang-3 was elevated in cervical cancer cells, compared with normal cervical cells, and Ang-3 silencing inhibited human umbilical vein endothelial cell angiogenesis and integrin alpha v beta 3 (αvβ3). Results also showed that upregulated αvβ3 expression increases VEGF and VEGFR2 secretion and blood vessel formation, suggesting Ang-3 as a potential novel therapeutic target for treating cervical cancer [72]. In another study, Ang-4 was discovered to be overexpressed in ovarian cancer cells. Immunoprecipitation results suggested that Ang-4 suppression leads to VEGFR2/VE-cadherin/Src complex dissociation and phosphorylation of VEGFR2 in A2780 and CAOV3 ovarian cancer cell lines. Researchers concluded that Ang-4 silencing significantly inhibits tumor angiogenesis and progression [73].

3. Conclusion

Due to cancer’s global impact, understanding how cancer develops and progresses is critical. Cytokines are heavily involved in regulating several cancer developmental processes. Cytokines have profound effects on cells and may lead to pro- or anti-tumor activity, depending on environmental conditions and the presence of other cytokines. Overall, studies have shown that cytokines are powerful molecular players that often control angiogenesis. The impact and therapeutic potential of cytokines are beginning to be uncovered through already existing and developing cytokine-targeted therapies. In this review, we highlighted only a few cytokines involved in angiogenesis. Further research focusing on the intricate relationship between angiogenesis and cytokines will be required to increase our understanding of how cancer develops. Cytokine research will continue to play a key role in revealing the molecular mechanisms behind cancer development and angiogenesis.

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