Resistance Mechanisms of Anti-angiogenic Therapy and Exosomes-Mediated Revascularization in Cancer

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.

Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells

“…Exosomes are secreted by many types of cells (especially tumor cells), and they have been reported to be closely correlated with cancer progression ( Zeng and Fu, 2020 ; Wang et al, 2021 ). Previous studies revealed that exosomes could construct a microenvironment which can induce the cancer progression via the association between cancer cells and surrounding stromal cells ( Yeon et al, 2019 ; Chen C. et al, 2020 ).…”

“…Previous reports have revealed that the association between tumor cells and stroma cells in tumor microenvironment can play a key role in modulating the development of cancer ( Maia et al, 2020 ; Zeng and Fu, 2020 ). In tumor environment, macrophages are often associated with tumor cells to regulate tumorigenesis and metastasis of cancers ( Li et al, 2020b ; Wang and Ilyas, 2020 ).…”

Identification of a 9-gene signature related to stemness for prognosis in hepatocellular carcinoma basing on weighted gene coexpression network analysis

“…All the 9 hub genes were highly expressed in LIHC samples, and their higher expressions were correlated with C1, C2, and C4, indicated they promote angiogenesis, M1/M2 macrophage polarization, and M2 response, thus associated with prognosis of HCC. Angiogenesis is critical for tumor development and therapy resistance (Zeng et al, 2019;Zeng and M.Fu, 2020). Further function and mechanism investigations need to be taken out for validating the roles of those hub genes.…”

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

“…Angiogenesis depends on cancer EVs cooperation via their miRNAs and positive factors (vascular endothelial growth factor and matrix metalloproteinases), together with the suppression of another factor inhibiting the hypoxia-inducible factor [ 77 ]. The ensuing effect is an activation of angiogenic signaling pathways in normal endothelial cells, with ensuing formation of new cancer vessels, where endothelial cells are differentiated from CSCs [ 25 , 77 , 78 ]. Immunoblocking of angiogenesis, a sedative process of cancer progression, could be prevented in TMEsby the crosstalk of stem cells with immune cells [ 79 ].…”