Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

Haibe, Yolla; Kreidieh, Malek; Hajj, Hiba El; Khalifeh, Ibrahim; Mukherji, Deborah; Temraz, Sally; Shamseddine, Ali

doi:10.3389/fonc.2020.00221

Cited by 272 publications

(229 citation statements)

References 306 publications

(244 reference statements)

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“…Downregulation of VEGF through gene therapy may reduce tumor growth and even lead to tumor shrinkage by inhibiting tumor angiogenesis and metastasis. 22 However, recent studies have shown that tumor revascularization and recurrence often occur after VEGF blockade treatment, and the escape mechanisms are mainly thought to be due to the upregulation of alternative proangiogenic cytokines. 11,15 Ang-2, which is mainly upregulated in endothelial cells and some malignant cells, is considered to be an important proangiogenic molecule during tumor development and metastasis.…”

Section: Discussionmentioning

confidence: 99%

<p>Effect of Chitosan Magnetic Nanoparticles Loaded with Ang2-siRNA Plasmids on the Growth of Melanoma Xenografts in Nude Mice</p>

Shan

et al. 2020

CMAR

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Angiopoietin-2 (Ang-2) has been proven to be a potential agent for malignant cancer treatment. The aim of the current study was to investigate the inhibitory effects of chitosan magnetic nanoparticles (CMNPs) loaded with Ang-2 small interfering RNA (Ang2-siRNA) plasmids (Ang2-CMNPs) on malignant melanoma. Materials and Methods: Melanoma-bearing nude mice were treated with Ang2-CMNPs and control CMNPs. Tumor volumes in each group were recorded. Real-time fluorescence quantitative-PCR was used to measure the relative Ang-2gene expression. Angiogenesis and Ang-2 expression in tumors were measured by immunohistochemistry. Cell apoptosis in each group was measured by TUNEL staining, and the expression of Bax, Bcl-2 and cleaved caspase-3 was analyzed by immunohistochemistry. Results: The progression of melanoma was significantly inhibited by Ang2-CMNP treatment. Ang2-CMNP treatment efficiently inhibited tumor growth and in-situ Ang-2 expression compared with those of the control group. Furthermore, Ang2-CMNP treatment significantly inhibited tumor angiogenesis and promoted cell apoptosis by regulating the Bax/Bcl-2 ratio and increasing cleaved caspase-3 expression in vivo. Conclusion: In summary, Ang2-CMNP treatment increased the regression of normalappearing vessels in the tumor microenvironment and induced the melanoma cells apoptosis through the mitochondrial apoptotic pathway, suggesting the potential clinical use of Ang2-CMNPs in malignant melanoma treatment.

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Section: Discussionmentioning

confidence: 99%

<p>Effect of Chitosan Magnetic Nanoparticles Loaded with Ang2-siRNA Plasmids on the Growth of Melanoma Xenografts in Nude Mice</p>

Shan

et al. 2020

CMAR

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“…Breast or pancreatic cancers for example rely on these angiogenic factors rather than on VEGFA and are poor responders to bevacizumab (Casanovas et al, 2005). Moreover, preclinical and clinical studies showed that anti-VEGFA antibodies and tyrosine-kinase inhibitors of VEGF receptors stimulate the production of these different growth factors (van Beijnum et al, 2015;Falcon et al, 2016;Haibe et al, 2020).…”

Section: Redundant Angiogenic Pathways and Hypoxiamentioning

confidence: 99%

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Montemagno

Pagès

2020

Front. Cell Dev. Biol.

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Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.

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“…It has been proposed earlier that TECs are mainly derived from sprouting of the pre-existing host vessels via angiogenesis, which were dependent on vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) (Jain and Carmeliet, 2012). However, the current therapeutic effects of anti-VEGF/VEGFRs agents are transient and, eventually, bring about drug resistance in a substantial patient population, including that of liver cancer patients (Sampat and O'Neil, 2013;Haibe et al, 2020). It is therefore urgent to elucidate the novel molecular mechanisms of tumor neovascularization and the origin of TECs toward making a breakthrough against the limitations of anti-angiogenic therapy.…”

Section: Introductionmentioning

confidence: 99%

Oct4 Regulates the Transition of Cancer Stem-Like Cells to Tumor Endothelial-Like Cells in Human Liver Cancer

Liu

Tang

Yang

et al. 2020

Front. Cell Dev. Biol.

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Octamer-binding transcription factor 4 (Oct4) has been recently implicated as a proangiogenic regulator in several induced pluripotent stem cells (iPSCs), however, its role in cancer stem-like cells (CSCs) remain unclear. We report here that Oct4 participates in tumor vasculogenesis in liver CSCs (LCSCs). We identify that LCSCs possess the potential of endothelial trans-differentiation under endothelial induction, present endothelial specific markers and their functions in vitro, and participate in neovasculogenesis in vivo. The knockdown of the Oct4A by short hairpin RNA (shRNA) in LCSCs represses endothelial trans-differentiation potential, but induces endothelial lineage-restricted differentiation, the latter is positively regulated by Oct4B1. Furthermore, Oct4 regulates vasculogenesis in LCSCs may be via the AKT-NF-κB-p65 signaling pathway. This work reveals Oct4, which is a crucial regulator, plays a critical role in tumor endothelial-like cells transition of LCSCs through Oct4A and Oct4B1 by different ways. The simultaneous inhibition of both the isoforms of Oct4 is hence expected to help regress neovascularization derived from CSCs. Our findings may provide insights to the possible new mechanisms of tumor vasculogenesis for primary liver cancer.

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Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

Cited by 272 publications

References 306 publications

<p>Effect of Chitosan Magnetic Nanoparticles Loaded with Ang2-siRNA Plasmids on the Growth of Melanoma Xenografts in Nude Mice</p>

<p>Effect of Chitosan Magnetic Nanoparticles Loaded with Ang2-siRNA Plasmids on the Growth of Melanoma Xenografts in Nude Mice</p>

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Oct4 Regulates the Transition of Cancer Stem-Like Cells to Tumor Endothelial-Like Cells in Human Liver Cancer

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