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Review
. 2021 Apr 5;22(7):3765.
doi: 10.3390/ijms22073765.

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

Filipa Lopes-Coelho  1   2 , Filipa Martins  1   2 , Sofia A Pereira  2 , Jacinta Serpa  1   2
Affiliations
Review

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

Filipa Lopes-Coelho et al. Int J Mol Sci. .

Abstract

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.

Keywords: VEGF; anti-angiogenic therapy; cancer therapy; drug resistance; neo-angiogenesis; new targets.

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Conflict of interest statement

The authors disclose any conflict of interest.

Figures

Figure 1
Figure 1
Pro-angiogenic factors released by cancer cells and tumor microenvironment (TME) are essential for neo-angiogenesis promotion, tumor growth, vascular co-option or vascular mimicry. Neo-angiogenesis is stimulated by the release of pro-angiogenic factors by cancer cells or by other cells in the tumor microenvironment (TME), as macrophages, stromal cells, and fibroblast. Among the positive regulators, vascular endothelial growth factor (VEGF) is the most well-studied, and it is almost ubiquitously present at angiogenesis sites. Once it binds to its tyrosine kinases receptors (VEGFRs), they become activated and form homo- or heterodimers, triggering intracellular signaling cascades to stimulate ECs’ proliferation, migration, differentiation, tube formation, and permeability control. Besides VEGF, other pro-angiogenic factors as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), placental growth factor (PIGF), and hepatocyte growth factor (HGF) are essential for endothelial tip cell activation (endothelial cell (EC)) that respond and guide EC migration in the direction of a pro-angiogenic stimulus, thereby promoting neo-angiogenesis). Moreover, a key process during EC migration is the formation of filopodia (actin-rich cellular protrusions) in tip cells, that will guide ECs towards the pro-angiogenic rich microenvironment. Nowadays, the employment of anti-angiogenic drugs for cancer treatment has been disappointing, in part because most drugs are VEGF-centered. VEGF blockade triggers compensatory mechanisms, such as the upregulation of other pro-angiogenic factors expression and the activation of other angiogenic signaling pathways, leading to patient resistance to VEGF signaling pathway blockade. During vascular co-option, tumor cells migrate along the preexistent blood vessels (specially tumor cells, rich in myofibroblasts), taking over of the existing vasculature to tumor blood supply. This process is essentially reported in highly vascularized tumors, as brain, lung, and liver. Vascular mimicry is characterized by a phenomenon resembling tumor blood supply independently of angiogenesis or endothelial cells (ECs), being correlated with poor patient survival. During this process, cancer cells acquire endothelial-like properties and organize into vascular-like structures acting as a system to obtain nutrients and oxygen, independently of normal blood vessels or neo-angiogenesis. FGF: Fibroblast growth factor; FGFR: Fibroblast growth factor receptor; HGF: Hepatocyte growth factor; PDGF: Platelet-derived growth factor; PDGFR: Platelet-derived growth factor receptor; PIGF: Placental growth factor; PIGFR: Platelet-derived growth factor receptor; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.
Figure 2
Figure 2
Anti-angiogenic drugs can act as decoy agents, monoclonal antibodies, or tyrosine kinase inhibitors. Bevacizumab was the first anti-angiogenic drug approved for human use, however, its use as monotherapy is inefficient. Compensatory mechanisms of other angiogenic mediators induces a switch in the vascular endothelial growth factor (VEGF)-dependent state to a VEGF-independent angiogenic process and leads to patient resistance to VEGF signaling pathway blockade. Nowadays, a new class of drugs, by blocking other effectors in angiogenic signaling pathways, try to improve the clinical efficacy of anti-angiogenic therapies. In some scenarios, the use of anti-angiogenic therapies delays the disease outcome of cancer patients, still other patients do not have any additional benefits. The major signaling pathways downstream of VEGFRs, FGFRs, PDGRs, and c-MET in endothelial cells (ECs) are PI3K-AKT-mTOR, Ras-Raf-MEK-ERK, and JAK-STATs, which are pivotal for EC survival, proliferation, and migration. AKT: Protein kinase B; ERK: Extracellular-signal-regulated kinase; FGF: Fibroblast growth factor; FGFR: Fibroblast growth factor receptor; HGF: Hepatocyte growth factor; JAK: Janus protein tyrosine kinase; MEK: Mitogen-activated protein kinase; mTOR: Mammalian target of rapamycin; PDGF: Platelet-derived growth factor; PDGFR: Platelet-derived growth factor receptor; PI3K: Phosphoinositide 3-kinases; Raf: Serine/Threonine Kinase; STAT: Signal transducer and activator of transcription protein; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor.
Figure 3
Figure 3
Increased oxidative stress activates endothelial cells (ECs) and kills cancer cells, and antioxidant mechanisms can stabilize vessels and improve anti-cancer chemotherapy. (A) A pro-angiogenic oxidative microenvironment, through the increased generation of ROS, the accumulation of lipid peroxides and glutathione (GSH) depletion is implicated in the promotion of ECs hyperactivation, vessels leakiness, and cancer cells migration and intravasation. (B) ROS scavenging activity is anti-angiogenic, since on one hand, it impairs the ECs activation, and on other hand, it promotes vessels normalization, pivotal to impair metastasis and improve the delivery of chemotherapeutic agents.
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