Typically, angiogenesis occurs under physiological circumstances, such as those that arise during embryonic development, wound healing, bone repair, and regeneration ^[1][2]. Additionally, specific pathological entities such as tumors, immune system disorders, inflammatory conditions, and hematological diseases can cause it. A key factor in the development and progression of disease is pathological angiogenesis. It plays a crucial part in the development of tumors, primarily by delivering nutrients and oxygen to tumor cells, aiding in their spread, and creating an immunosuppressive tumor microenvironment that results in tumor evolution ^{[2][3][4][5][6]}[1,3,4,35,36]. Recent studies suggest that disruption of the equilibrium between activine A and its naturally occurring inhibitor, follistatin, is one of the pro-angiogenic pathogenic pathways in TET. High follistatin levels were observed in TC patients and were related to tumor microvessel density and advanced tumor stage ^[5][35]. Because every tissue has unique properties and vascular characteristics that set separate organs apart, it is believed that different tumor types use different genetic processes to generate blood circulation, depending on their stage of development and environment ^[7][9]. The neoplastic cell can release sequestered growth factors or their receptors from the extracellular matrix, or it can attract inflammatory cells like mast cells and macrophages, which are both abundant sources of cytokines and angiogenetic factors. A rich source of angiogenic agents, platelets are also frequently found in higher concentrations in malignant diseases. Tumor endothelium or epithelium can activate platelets ^[7][8][9,37]. The first soluble angiogenic factor, tumor angiogenesis factor (TAF), was identified by Folkman et al. in 1971 ^[9][38]. The VEGF family, which presently consists of placental growth factor and VEGF-A to VEGF-D, is involved in a variety of human tumor types ^[10][39]. These bind variably to three high-affinity endothelial-cell tyrosine kinase receptors: flt-1 (VEGFR1), KDR (VEGFR2), and flt-4 (VEGFR3) ^[7][9]. This complicated cascade allows the VEGFs to have many effects, such as increasing vascular permeability (which results in increasing tumor stroma development), endothelial cell proliferation, and tube formation. Many tumors of the lung, brain, gastrointestinal system, and urogenital tract express VEGF-A at high levels. The correlation between expression and microvessel density and prognosis demonstrates the significance of VEGF-A in human malignant illness. The other VEGFs’ function in human disease is still being investigated, though ^[7][10][9,39]. It is now understood that a tumor’s net angiogenic activity is determined by the ratio of angiogenic stimulators to inhibitors. Thus, angiogenesis may be caused by the overexpression of favorable factors and/or the suppression of a number of naturally occurring inhibitors ^[7][9]. Numerous distinct cells create angiogenetic growth factors, which have a close role in both tumor angiogenesis and development. Angiogenic growth factors, including VEGF, FGF, and angiopoietin, are crucial for the process of angiogenesis ^[11][40]. These growth factors are produced by various cell types and include a diverse range of proteins in addition to VEGF and FGF: platelet-derived growth factor, tumor necrosis factor, insulin-like growth factor-1, transforming growth factor, angiogenin, hepatocyte growth factor, placental growth factor, and several others. The FGF and VEGF families of angiogenetic growth factors have been studied the most out of all of those that have been identified.

2. Fibroblast Growth Factor

These molecules are essential to the process of angiogenesis because they promote the growth of both fibroblasts and endothelial cells. They are also involved in at least three of the four stages of wound healing: inflammation, repair, and regeneration. Tumor formation and progression are among the other significant roles played by FGFs. The two isoforms that have been studied the most are FGF-1 and FGF-2 ^[11][40].

3. Vascular Endothelial Growth Factor

There are currently at least five members of the VEGF family, and three VEGF receptors (VEGFR) mediate their activities. Transmembrane receptor tyrosine kinases (RTKs) allow these receptors to communicate with the interior of cells ^[7][11][12][9,40,41].

4. VEGF Receptors

In humans, VEGFR-1 and VEGFR-2, two high-affinity membrane-spanning receptors, mediate the actions of VEGF on endothelial cells ^[7][11][12][9,40,41].

5. Side Effects in Anti-Angiogenic Therapy

Angiogenesis inhibitors have been linked to possible disruptions of numerous physiological functions, including blood pressure, kidney function, wound healing, fetal development, reproduction, and an increased risk of thrombi in the arteries that could cause a heart attack or stroke. For instance, one of the most common adverse effects of systemic VEGF signaling suppression is hypertension, which is also one of the easiest to control when using prescription anti-hypertensive drugs. When VEGF signaling is inhibited in cancer treatment, the resulting reduction in VEGF levels causes endothelial dysfunction and ultimately leads to hypertension ^[12][41].

6. Categories of Angiogenesis Inhibitors

The development of new blood vessels can be prevented by angiogenesis inhibitors, which would stop tumor growth but not completely eradicate it. Consequently, anti-angiogenesis monotherapies do not work as well in humans as was anticipated. Combinatorial therapies using traditional chemotherapeutic medications are therefore necessary ^[1][13][2,42]. There are two primary categories of angiogenesis inhibitors: (i) direct inhibitors, which act on endothelial cells inside the expanding vasculature, and (ii) indirect inhibitors, which act on tumor cells or other stromal cells linked with tumor growth ^[12][41]. Direct inhibitors of angiogenesis include angiostatin, endostatin, arrestin, canstatin, and tumstatin. They impede the proliferation and migration of vascular endothelial cells in response to certain activators of angiogenesis, such as VEGF, bFGF, IL-8, and PDGF ^[14][15][43,44]. Endogenous inhibitors that directly target those signaling pathways were believed to have the lowest potential to develop resistance to drugs because they attack genetically stable endothelium cells rather than unstable tumor cells that are mutating. However, in randomized phase III trials, endostatin has not yet been shown to benefit patients in any way, and, in phase II trials, it has not even produced moderate action ^[14][16][43,45]. On the other hand, pro-angiogenic proteins like EGFR will not express or function when indirect angiogenesis inhibitors are used ^[15][44]. Gefitinib, an EGFR TKI, has been used as a treatment in different human cancers (colon, ovary, and breast) ^[17][46]. In general, small-molecule tyrosine kinase inhibitors (TKIs), VEGF decoy receptors, and monoclonal antibodies are the three main groups of medicines that target VEGF that have been produced ^[18][47]. Currently, these drugs are being studied or used in clinical settings either alone or in conjunction with radiation or cytotoxic chemotherapy.

6.1. Anti-VEGF Monoclonal Antibodies

Bevacizumab is a recombinant humanized monoclonal antibody against VEGF and inhibits VEGF-A produced by tumor cells, thus hindering the formation of new blood vessels and ultimately causing tumor starvation and growth suppression ^[19][48]. However, combining bevacizumab with chemotherapy has been shown to exacerbate its negative effects. As already mentioned, the administration of bevacizumab is validated in randomized phase III trials for the treatment of colorectal cancer in conjunction with chemotherapy. FDA approval was attributed to bevacizumab for the treatment of advanced non-small-cell lung cancer of non-squamous histological type ^[20][21][49,50]. Glioblastoma, renal cell carcinoma, and metastatic HER2-negative breast cancer are other cancer types in which the administration of bevacizumab is assessed for treatment ^{[22][23][24][25]}[51,52,53,54]. A systematic review provided data about the adverse events related to the use of bevacizumab in colorectal cancer patients ^[26][55]. The four categories of adverse effects include hematological, cardiovascular, gastrointestinal, and other. Cardiovascular complications include coronary artery disease, myocardial infarction, arrhythmias (atrial fibrillation and atrioventricular block), arterial hypertension, and thromboembolic events, even though the latter occur less frequently. The most important gastrointestinal complication is perforation of the digestive tube. When bevacizumab is added to chemotherapy, bleeding occurs more frequently. Neutropenia, febrile neutropenia, anemia, and thrombocytopenia are among the reported hematological complications.

6.2. VEGF Decoy Receptor

Aflibercept inhibits VEGF-A, VEGFB, and PIGF2 and has a stronger affinity for VEGF-A than BEV. Phase I–II trials encouraged more research on the use of aflibercept in conjunction with chemotherapy for a variety of cancer types ^[18][47]. Adverse events such as diarrhea, asthenia, hypertension, proteinuria, infections, and neutropenia are related to the administration of aflibercept in patients presenting metastatic colorectal cancer ^[27][56].

6.3. Small-Molecule Inhibitors

The biochemical function of the downstream VEGFR-mediated signaling tyrosine kinases can be potently and selectively inhibited by small-molecule tyrosine kinase inhibitors (TKIs), particularly the multi-target kinase inhibitors. These multi-targeted oral TKIs are thought to have a wide range of inhibitory effects on tumor angiogenesis and growth. They target angiogenesis pathways, such as VEGFR, PDGFR, FGFR, c-KIT, FLT-3, etc. ^{[28][29][30][31]}[57,58,59,60]. Imatinib is a selective inhibitor of Bcr/Abl, and it is approved for the treatment of hematological malignancies and gastrointestinal stromal tumors. Sorafenib targets VEGFR-2 and -3, PDGFR-b, Flt-3, and c-Kit and is used in the treatment of hepatocellular carcinoma and renal cell carcinoma. Toxicities include diarrhea, rash, nausea, cardiac ischemia, or infarction ^[18][47] Sunitinib is a multi-TKI that targets VEGFR-1–3, PDGFR, Flt-3, and c-Kit79. It was first used for the treatment of GIST after failure of treatment with imatinib, and it was later approved for metastatic renal cell carcinoma ^[18][47]. Axitinib is a potent second-generation inhibitor of VEGF-1, 2, and 3. In contrast to first-generation inhibitors, it has better VEGF-specific selectivity and does not block PDGF, b-RAF, FLT-3, and KITor other off targets. It is mostly used in the case of renal cell carcinoma. Toxicities include diarrhea, hypertension, fatigue, nausea, and dysphonia ^[18][47]. Lenvatinib is a multiple-receptor TKI of VEGFR1-3, FGFR1-4, KIT (tyrosine-protein kinase KIT or mast/stem cell growth factor receptor), platelet-derived growth factor receptor a (PDGFRa), and RET ^[18][47]. Anlotinib is a multiple-kinase inhibitor that has demonstrated effectiveness against different cancer types. Its use has recently gained interest against certain types of thyroid malignancies ^[32][61]. There is some evidence that angiogenesis plays a significant part in thymic epithelial malignancies. VEGF is overexpressed in these cancers, and microvessel density and VEGF expression are related to invasiveness and stage ^[6][33][34][36,62,63]. Patients with TC have been found to have higher serum levels of VEGF and b-FGF ^[35][31]. Additionally, in thymic epithelial cells, PDGF and PDGFR are overexpressed ^[36][64]. VEGF-, KIT-, or PDGF-targeting medications may be effective in treating TET according to anecdotal findings ^[37][18]. Three of the four patients with TC showed responses to sunitinib and multiple-receptor tyrosine kinase activation according to research by Strobel et al. ^[38][19]. Lattanzio et al. used immunohistochemistry to assess the expression of possible molecular targets of anti-angiogenic therapy, such as VEGFA, VEGFC, VEGFD, VEGFR1, VEGFR2, VEGFR3, and PDGFRβ, in a Tissue Micro Arrays series of 200 TET [3]. B3 thymomas and TC expressed significantly higher levels of both VEGFA and VEGFC compared to A, AB, and B1 thymomas. Additionally, compared to stage I and stage II tumors, stage IV tumors displayed a larger proportion of VEGFA- and VEGFC-positive cells [3]. Lenvatinib, an anti-angiogenic TKI investigated in phase II trials, demonstrated efficacy in TC, with a remarkable ORR. Also, sunitinib showed a high response rate and may therefore be a good option. Based on comparison between trials, which should be conducted cautiously, it has been considered that lenvatinib attained a higher response rate in comparison to other drugs, with a better toxicity profile. Lenvatinib may be more effective because it acts by inhibiting different tyrosine kinase receptors, such as VEGFR2, and different pharmacodynamic features could possibly be involved ^[39][28]. In clinical trials, sunitinib has been reported to be beneficial against metastatic clear-cell renal carcinoma ^[40][65], gastrointestinal stromal tumors ^[41][66], and advanced pancreatic neuroendocrine tumors ^[42][67]. The efficacy of sunitinib in TET was encouraging, and, as a result, sunitinib has been recommended as an option in the European Society of Medical Oncology (ESMO) guidelines ^[43][68]. Disappointingly, the investigators of the Resound trial were not able to identify a subset of patients potentially benefiting from regorafenib. In fact, no difference was observed in terms of DCR, PFS, or OS stratifying for age, histology, sex, response to the previous line, and line of therapy ^[44][20]. Grade 3 and 4 treatment-related AE, dose reduction, and definitive drug interruption were observed in ten (52.6%), nine (47.4%), and three (15.8%) of nineteen patients treated with regorafenib, respectively. These results are similar to those achieved by sunitinib (grade 3–4 treatment-related AEs 70%; dose reduction 65%; definitive drug interruption 18.5%) and lenvatinib (grade 3–4 treatment-related AEs 64%; dose reduction 100%; definitive drug interruption 17%) ^[39][45][46][21,22,28]. No grade 5 treatment-related AEs were observed with regorafenib ^[44][20]. For patients with TET, new small-molecule TKI with anti-angiogenic action are being investigated. Anlotinib is a new oral TKI with a broad therapeutic index that can effectively inhibit VEGFR, PDGFR, FGFR, and c-kit. Anlotinib exhibits significant VEGF receptor VEGFR2 and VEGFR3 selectivity ^[35][47][48][31,69,70]. However, there are mainly retrospective series reporting on their efficacy in the treatment of TET. On the other hand, a recent phase II trial assessing apatinib in stage IV TET ^[49][30] yielded encouraging results. RELEVENT is a multicentric open-label phase 2 study (NCT03921671) ^[31][60]. Patients with TET of any histological type will be enrolled in this trial. Its objective is to evaluate the activity and safety of the combination of ramucirumab (10 mg/kg) plus carboplatin (AUC 5) and paclitaxel (200 mg/m²) in patients with relapsed and/or metastatic TC/thymoma B3 after first-line treatment ^[31][60]. Ramucirumab is a fully human monoclonal antibody (IgG1) that acts as a direct VEGFR2 antagonist that binds with high affinity to the extracellular domain of VEGFR2 and blocks the binding of natural VEGFR ligands (VEGF-A, VEGF-C, and VEGF-D) ^[50][71]. Pro-angiogenic factors cause dysregulated pathological tumor vasculature’s progression. Consequently, the tumor microenvironment is characterized by hypoxia, acidity, patchy hypoperfusion, and high interstitial fluid pressure. Tumor vasculature is also characterized by structural abnormalities [4]. All these variables may have a major impact on the immunotherapeutic response and may have an impact on immune cell survival, infiltration, proliferation, and function, suppressing the tumor microenvironment. Immune cell infiltration and function in the tumor microenvironment play a significant role in immunotherapy efficacy. The ability of anti-angiogenesis to normalize blood vessels in tumors was subsequently identified through ongoing research, and this offered the rationale for combining it with a variety of anti-tumor medicines [4]. The use of immunotherapy and vascular normalization therapy as standalone treatments for tumors has recently become increasingly important, although each faces a number of obstacles. Numerous studies have uncovered intricate regulatory relationships between an immunosuppressive tumor microenvironment and aberrant angiogenesis, and they have also confirmed the therapeutic efficacy of immunotherapy and anti-angiogenesis treatment when used in combination ^[2][4][51][1,4,72]. The importance and efficiency of this combined strategy have also been supported by an increasing number of clinical trials. Immunotherapy is probably more successful when combined with vascular normalization therapy, which can also decrease adverse effects and extend patients’ survival ^[2][1]. Pembrolizumab in conjunction with sunitinib or lenvatinib in patients with TC is being studied in two phase II trials (NCT03463460 and NCT04710628) ^[52][53][73,74]. In a different phase I/II study, patients with thoracic malignancies, including TC, will be administered oral VEGFR/PDGFR TKI vorolanib in combination with nivolumab (NCT03583086) ^[54][75]. The ongoing trials registered in clinicaltrials.gov are demonstrated in Table 1. Treatment with the combination of immune checkpoint inhibitors (ICI) and small-molecule anti-angiogenic drugs showed encouraging results in some solid tumors ^[55][56][76,77]. Therefore, it is necessary to continue research on innovative combinations of ICIs and small-molecule anti-angiogenic medications in patients with recurrent TC.