Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis.

Bochao Geng,Aihua Sui,Wenjuan Luo,Jingyi Bai,Yuanzhang Zhu,Zhizhi Dou,Yingying Yuan

doi:10.3389/fonc.2021.714646

Bochao Geng, Aihua Sui + Show 5 more

Open Access

https://doi.org/10.3389/fonc.2021.714646

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Abstract

Angiogenesis and vasculogenic mimicry (VM) are considered to be the main processes to ensure tumor blood supply during the proliferation and metastasis of choroidal melanoma (CM). The traditional antimalarial drug artesunate (ART) has some potential anti-CM effects; however, the underlying mechanisms remain unclarified. Recent studies have shown that the Wnt5a/calmodulin-dependent kinase II (CaMKII) signaling pathway has a close correlation with angiogenesis and VM formation. This study demonstrated that ART eliminated VM formation by inhibiting the aforementioned signaling pathway in CM cells. The microvessel sprouting of the mouse aortic rings and the microvessel density of chicken chorioallantoic membrane (CAM) decreased significantly after ART treatment. VM formation assay and periodic acid schiff (PAS) staining revealed that ART inhibited VM formation in CM. Moreover, ART downregulated the expression levels of the angiogenesis-related proteins vascular endothelial growth factor receptor (VEGFR) 2, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor (VEGF) A, and VM-related proteins ephrin type-A receptor (EphA) 2 and vascular endothelial (VE)-cadherin. The expression of hypoxia-inducible factor (HIF)-1α, Wnt5a, and phosphorylated CaMKII was also downregulated after ART treatment. In addition, we further demonstrated that ART inhibited the proliferation, migration, and invasion of OCM-1 and C918 cells. Collectively, our results suggested that ART inhibited angiogenesis and VM formation of choroidal melanoma likely by regulating the Wnt5a/CaMKII signaling pathway. These findings further supported the feasibility of ART for cancer therapy.

Highlights

Choroidal melanoma (CM) is a common intraocular malignancy; up to 50% of patients with CM die from metastases [1]
vasculogenic mimicry (VM) is a new tumor microcirculation mode formed by highly aggressive tumor cells, which differs from the traditional endothelium-dependent angiogenesis; it is closely related to tumor cell invasion, migration, and poor clinical prognosis [20, 21]
A combined therapy targeting VM formation and angiogenesis based on its incentives to prevent tumor blood supply urgently needs to be developed

Summary

Introduction

Choroidal melanoma (CM) is a common intraocular malignancy; up to 50% of patients with CM die from metastases [1]. Radiotherapy is the most common globe-conserving therapy for CM, but the irradiated tumor often causes exudation and overproduction of angiogenic factors, Artesunate Suppressed Choroidal Melanoma Angiogenesis leading to optic disk neovascularization and neovascular glaucoma [3]. The main mechanism of neovascularization in CM is angiogenesis, which involves the sprouting of existing endothelial cells to form new neoplastic capillaries. Some invasive tumor cells usually reside far away from the area where the primary tumor is located, and cannot be completely eliminated by surgery. These residual CM cells can induce VM formation, leading to CM recurrence. Based on the close relationship between VM and tumor microenvironment, targeting VM inhibitors combined with antiangiogenic therapies in CM seems to be an attractive and potentially effective strategy

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