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.

Final Remarks

The failure of anti-VEGF strategies in the control of cancer can be in part related to two major factors. On one hand, the fact that the precise molecular mechanisms of cancer neo-angiogenesis still have secrets. On the other hand, because the abrogation of blood supply will also restrict drug delivery to the tumor, decrease their efficacy, and promote drug resistance [9]. In line, the paradox in the use of anti-angiogenic drugs arises from new findings showing that instead of eradicating blood supply, strategies focused on restoring the tumor vessels normalization would increase the delivery of therapeutic agents to cancer cells, improving the therapeutic efficacy and impairing cancer cells spread [125].

Interestingly, simvastatin, a statin with antioxidant properties, has been showed to reduce hypoxia-induced endothelium leakage and decrease ROS-induced HIF1α and VEGF expression, attenuating VEGF-derived tumor vessel hyperpermeability and improving cisplatin and cyclophosphamide efficacy [241]. In a theoretical scenario, cancer treatment might rely on multi-mechanisms targeting strategies focused on the induction of cancer cells death and in the promotion of tumor vascular regression or stabilization events (Figure 3). At the same time, these strategies will transform the remaining vessels into a more functional vascular network with decreased permeability, promoting drug delivery and impairing metastasis. Cancer cells under a certain threshold have adaptive antioxidant mechanisms controlling oxidative stress, however, above this threshold, ROS accumulation disrupts redox homeostasis and causes severe damage in cancer cells, ultimately leading to cell death [242]. Given these results, strategies to enhance lethal ROS production in cancer cells have a promising anti-cancer effect.

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.

Angiogenesis-based cancer therapeutic strategies must accompany the microenvironmental and metabolic drift, which tumor cells (malignant and stromal) undergo in order to progress. Therefore, by presenting different metabolic patterns and adaptive redox mechanisms, ECs and cancer cells would present a disparate behavior, and whereas oxidative stress activates ECs and stabilizes blood vessels that will be more competent in drugs delivery; cancer cells would be endangered by oxidative stress and by drugs aggression.