Anti-Angiogenic Cancer Treatments

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Aya Elmeligy

Angiogenesis is the formation of blood vessels within the body to provide oxygen and nutrients to tissues. Tumors will hijack this process to allow for continued growth and metastasis by forming their own vascular system. Microvessel density within a tumor is often used as a prognosis tool, as the more vessels present within a tumor, the more aggressive it is. Under normal conditions, the formation of blood vessels is initiated by Vascular Endothelial Growth Factors (VEGFs) released by tissue requiring oxygen. VEGFs bind to receptors on nearby endothelial cells leading to vessel formation and cell proliferation. VEGF levels correlate with microvessel density and therefore indicate the severity of cancer. Angiogenesis is kept in check by various activators and inhibitors forming the ‘Angiogenic Switch’; this balance is disrupted in cancers by the upregulation of activators or blocking of inhibitors. This pathological angiogenesis can be prevented by targeting activators of angiogenesis in cancers.

Anti-angiogenic therapies are an old and known treatment strategy but, like any research area, studies constantly look to build and improve on this. One of the first anti-angiogenic drugs, Bevacizumab (Avastin) was aimed at preventing VEGFA from binding to its receptor VEGFR2, consequently blocking its signaling pathway and endothelial cell proliferation.  Combined with chemotherapy, anti-angiogenic therapies are the standard for treating breast, kidney, and non-small cell lung cancers. Other common targets for these drugs include matrix metalloproteinases (MMPs), which degrade the basement membrane and remodel the extracellular matrix (ECM) to allow for endothelial cell migration. MMPs are associated with the liberation of various growth factors often found within the ECM that allows the continuation of the angiogenic cascade. Many drugs aimed at inhibiting MMPs fail at the clinical stage due to the role MMPs have at producing angiogenesis inhibitors; therefore, by blocking their action, angiogenesis is actually being promoted. As a long-term treatment, pharmacological interventions are often ineffective as the tumor adapts and acquires migratory phenotypes, such as the activation of hypoxia-inducible factor (HIF), vital in the tumor’s response to angiogenesis. HIF-1 signaling leads to the stabilization of HIF1-alpha and accumulation within the nucleus, which induces the production of activators of angiogenesis, such as VEGF and its receptors.

A study by Varone et al. examined how the angiogenic switch could favor the production of inhibitors in hypoxic conditions, which, mediated by HIF signaling, leads to tumor progression. The endoplasmic reticulum’s protein disulfide oxidase, endoplasmic oxidoreduction 1 (ERO1), works with protein disulfide isomerase to introduce disulfide bonds to new client proteins and secrete VEGFA as a disulfide-bonded homodimer. This VEGFA can bind to its receptor, activating angiogenesis as a result. The study aimed to investigate the effect of ERO1 knockout in cells on VEGF and, consequently, the ability of endothelial cells to migrate. They began by showing ERO1 levels were elevated in breast tumors compared to normal healthy breast tissue. ERO1 knockout breast cancer cells showed an ineffective ability to undergo angiogenesis in hypoxic conditions, and fewer blood vessels were seen within the breast tumor. This study is the basis for potentially using ERO1 inhibitors as an anti-angiogenesis treatment; future research should aim to find selective ERO1 inhibitors.

Research has shown that angiogenesis can be mediated by short noncoding RNAs called microRNAs, which can negatively regulate gene expression post-transcriptionally. MicroRNAs specific to endothelial cells are termed angiomiRs and are often implicated in tumor progression via dysregulated angiogenesis. Of the four hundred miRNAs discovered within the human genome, around 10% are related to endothelial cell function and the angiogenic cascade. Examples of these include miRNA-210, which has a role in the production of VEGF and its receptor VEGFR2 during hypoxia conditions, ultimately initiating angiogenesis. Studies in which miRNA-210 was inhibited showed an increase in autophagy and apoptosis of tumor cells leading to reduced levels of angiogenesis. Due to this, miRNA-210 may be a possible target for cancer therapy. Many obstacles are present when targeting this microRNA, including issues with effective delivery to the specific cancer tissue, as there is a possibility of off-target delivery leading to toxicity. Currently, possible miRNA therapies are in phase III clinical trials and are still awaiting FDA approval; translation of treatments from bench to bedside is vital for the progression of this research.

Anti-angiogenic treatments are standard for cancer treatment, but as with many other therapies, tumors can adapt and become resistant. Continuous research into already established work is essential to stay one step ahead of cancer adaptations.

Edited by Rachel Cherney

References

Vafopoulou, P. and Kourti, M. (2022). Anti-angiogenic drugs in cancer therapeutics: a review of the latest preclinical and clinical studies of anti-angiogenic agents with anticancer potential. Journal of Cancer Metastasis and Treatment, [online] 8, p.18. doi:https://doi.org/10.20517/2394-4722.2022.08.

Varone, E., Decio, A., Chernorudskiy, A., Minoli, L., Brunelli, L., Ioli, F., Piotti, A., Pastorelli, R., Fratelli, M., Gobbi, M., Giavazzi, R. and Zito, E. (2021). The ER stress response mediator ERO1 triggers cancer metastasis by favoring the angiogenic switch in hypoxic conditions. Oncogene, 40(9), pp.1721–1736. doi:https://doi.org/10.1038/s41388-021-01659-y.

Yang, M., Zhang, Y., Li, M., Liu, X. and Darvishi, M. (2023). The various role of microRNAs in breast cancer angiogenesis, with a special focus on novel miRNA-based delivery strategies. Cancer Cell International, 23(1). doi:https://doi.org/10.1186/s12935-022-02837-y.

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