Abstract
Angiogenesis is a vital process for the growth and dissemination of solid cancers. Numerous molecular pathways are known to drive angiogenic switch in cancer cells promoting the growth of new blood vessels and increased incidence of distant metastasis. Several angiogenesis inhibitors are clinically available for the treatment of different types of advanced solid cancers. These inhibitors mostly belong to monoclonal antibodies or small-molecule tyrosine kinase inhibitors targeting the classical vascular endothelial growth factor (VEGF) and its receptors. Nevertheless, breast cancer is one example of solid tumors that had constantly failed to respond to angiogenesis inhibitors in terms of improved survival outcomes of patients. Accordingly, it is of paramount importance to assess the molecular mechanisms driving angiogenic signaling in breast cancer to explore suitable drug targets that can be further investigated in preclinical and clinical settings. This review summarizes the current evidence for the effect of clinically available anti-angiogenic drugs in breast cancer treatment. Further, major mechanisms associated with intrinsic or acquired resistance to anti-VEGF therapy are discussed. The review also describes evidence from preclinical and clinical studies on targeting novel non-VEGF angiogenic pathways in breast cancer and several approaches to the normalization of tumor vasculature by targeting pericytes, utilization of microRNAs and extracellular tumor-associate vesicles, using immunotherapeutic drugs, and nanotechnology.
Highlights
Angiogenesis is the process of the formation of new blood vessels from pre-existing ones (Teleanu et al, 2019)
The vascular endothelial growth factor (VEGF) family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (Yang et al, 2018). These ligands bind to their endothelial VEGF receptors (VEGFRs); VEGFR-1, VEGFR-2, and VEGFR-3, which belong to the family of receptor tyrosine kinases (RTKs) (Yang et al, 2018)
Recent evidence showed that the IL-6/IL-6R pathway is activated in hypoxic breast cancer cells and that inhibition of IL-6R using siRNA significantly blocked angiogenesis and invasion in different models (Bharti et al, 2018)
Summary
Angiogenesis is the process of the formation of new blood vessels from pre-existing ones (Teleanu et al, 2019). Several pro-angiogenic factors are known to drive vascular growth including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), angiopoietins (Angs), hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), and matrix metalloproteinases (MMPs). Among these factors, the VEGF family is considered a major regulator of vascular growth and angiogenesis (Rust et al, 2019).
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