Abstract
Angiogenesis is a key mechanism for tumor growth and metastasis and has been a therapeutic target for anti-cancer treatments. Intensive vascular growth is concomitant with the rapidly proliferating tumor cell population and tumor outgrowth. Current angiogenesis inhibitors targeting either one or a few pro-angiogenic factors or a range of downstream signaling molecules provide clinical benefit, but not without significant side effects. miRNAs are important post-transcriptional regulators of gene expression, and their dysregulation has been associated with tumor progression, metastasis, resistance, and the promotion of tumor-induced angiogenesis. In this mini-review, we provide a brief overview of the current anti-angiogenic approaches, their molecular targets, and side effects, as well as discuss existing literature on the role of miRNAs in angiogenesis. As we highlight specific miRNAs, based on their activity on endothelial or cancer cells, we discuss their potential for anti-angiogenic targeting in cancer as adjuvant therapy and the importance of angiogenesis being evaluated in such combinatorial approaches.
Highlights
Angiogenesis is the physiological process for new blood vessel development from pre-existing ones
Hypoxia leads to the secretion of many growth factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, cytokines, such as interleukin 8 (IL-8), and other pro-angiogenic
We provide representative examples of miRNAs with antiangiogenic properties that demonstrated anti-tumoral activity. miR-27b [115, 116] and miR-128 [69] suppress tumor progression and angiogenesis by targeting VEGF-C. miR-125b suppressed endothelial cells (EC) tube formation by inhibiting E-cadherin [117]. miR-192 targets EGR1 and HOXB9, leading to anti-tumor and anti-angiogenic activity in human ovarian epithelial tumors [118]. miR-200 family inhibited angiogenesis through direct and indirect mechanisms by targeting interleukin-8 (IL8) and CXCL1 secreted by the tumor endothelial and cancer cells [119]
Summary
Angiogenesis is the physiological process for new blood vessel development from pre-existing ones. We sought to explore the use of miRNAs for cancer treatment due to their ability to regulate angiogenesis and focus on their potential and utilization as adjuvant therapies with chemotherapeutics because of their anti-angiogenic properties. The striking impact on angiogenesis, vascular morphology, and functions upon VEGF inhibition or deficiency, along with its overexpression in most solid tumors, including lung, breast, liver, and ovarian cancers, brought it to the frontline of anti-angiogenic targets, where it remains till today. Bevacizumab is FDAapproved for colorectal cancer, non-small cell lung cancer, renal cell carcinoma, cervical, fallopian tube cancer, peritoneal cancer, and glioblastoma, whereas it failed to provide clinical benefit in the majority of the other cancer types, including breast cancer, for which the FDA approval lasted for a short period [2]. Vandetanib, targeting VEGFR, epidermal growth factor receptor (EGFR), RET, for medullary thyroid cancer
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