Abstract
Anti-angiogenic therapies (AATs) have been widely used for cancer treatment. But the beneficial effects of AATs are short, because AAT-induced tumor revascularization facilitates the tumor relapse. In this mini-review, we described different forms of tumor neovascularization and revascularization including sprouting angiogenesis, vessel co-option, intussusceptive angiogenesis, and vasculogenic mimicry, all of which are closely mediated by vascular endothelial growth factor (VEGF), angiopoietins, matrix metalloproteinases, and exosomes. We also summarized the current findings for the resistance mechanisms of AATs including enhancement in pro-angiogenic cytokines, heterogeneity in tumor-associated endothelial cells (ECs), crosstalk between tumor cells and ECs, masking of extracellular vesicles, matrix stiffness and contributions from fibroblasts, macrophages and adipocytes in the tumor microenvironment. We highlighted the revascularization following AATs, particularly the role of exosome stimulating factors such as hypoxia and miRNA, and that of exosomal cargos such as cytokines, miRNAs, lncRNAs, and circRNAs from the tumor ECs in angiogenesis and revascularization. Finally, we proposed that renormalization of tumor ECs would be a more efficient cancer therapy than the current AATs.
Highlights
Current anticancer therapies are hindered by two critical processes
Tumor angiogenesis is regulated by a variety of cytokines including vascular endothelial growth factor (VEGF), placenta growth factor (PLGF), transforming growth factor-β (TGF-β), tumor necrosis factor-α (TNF-α), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and angiopoietin (Galvano et al, 2019)
It was initially thought that anti-angiogenic therapies (AATs) were less likely to produce drug resistance, since researchers believed that endothelial cells (ECs) have a very stable genome, and endogenous angiogenesis inhibitors target ECs rather than tumor cells (Jayson et al, 2016)
Summary
One process is the local invasion and metastasis of cancer cells from either primary tumors or distant lesions. Another is imposed by the resistance to therapies including surgery, radiation and chemotherapy (Weinstein et al, 1991; Meads et al, 2009; Alexander and Friedl, 2012). AAT disrupts the vascular barrier to facilitate the invasion and metastasis of tumor cells, which drives acquired AAT resistance in cancers such as hepatocellular carcinoma (HCC) (Kuczynski et al, 2016; Angara et al, 2017). It was reported that tissue stiffness increased by metastasis-associated fibroblasts could enhance both angiogenesis and AAT resistance to bevacizumab in metastatic colorectal cancer (Shen et al, 2020). The aim of this mini-review is to summarize the key characteristics and roles of angiogenesis in cancer and highlight the acquired AAT resistance due to revascularization
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