Hypoxia promotes vasculogenic mimicry formation by inducing epithelial–mesenchymal transition in ovarian carcinoma

Du, Jing; Sun, Baocun; Zhao, Xiulan; Gu, Qing; Dong, Xueyi; Mo, Jing; Sun, Tao; Wang, Junyan; Sun, Ryan; Liu, Yanrong

doi:10.1016/j.ygyno.2014.02.034

Cited by 110 publications

(114 citation statements)

References 27 publications

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“…Snail and Slug belong to the superfamily of EMT transcriptional activators and have been proved to be involved in VM on hepatocellular carcinoma and epithelial ovarian carcinoma. [40][41][42] However, these factors had no significant relation with sunitinib-induced VM in TNBC MDA-MB-231and Hs578T tumors.…”

Section: Discussionmentioning

confidence: 93%

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Sun

Zhang

Yao

et al. 2017

Cancer Biology & Therapy

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Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials. Along with endothelium-dependent vessels, there is also vasculogenic mimicry (VM) in the microcirculation of malignant tumors. The role of VM is not completely understood regarding anti-angiogenic treatment. In this study, human TNBC MDA-MB-231 and Hs578T and non-TNBC MCF-7 and BT474 tumor-bearing mice were treated with sunitinib, an anti-angiogenic drug, using a clinically relevant schedule. The drug was administered for one week and then discontinued. Tumor growth and invasion were observed, and the microcirculation patterns were detected with PAS/endomucin staining. Moreover, hypoxia and VM-associated proteins were evaluated with Hypoxyprobe kits and immunohistochemistry, respectively. Sunitinib significantly inhibited tumor growth in the TNBC and non-TNBC tumors. However, MDA-MB-231 and Hs578T tumors regrew and were more aggressive when the treatment was stopped. The discontinuation had no significant effect on the behavior of the non-TNBC MCF-7 and BT474 tumors. The growth of endothelium-dependent vessels in the TNBC MDA-MB-231 and Hs578T tumors were blocked by sunitinib, during which the number of VM channels significantly increased and resulted in a rebound of endothelium-dependent vessels after sunitinib discontinuation. Moreover, the VM-associated proteins VE-cadherin and Twist1 upregulated in the sunitinib-treated MDA-MB-231 and Hs578T tumors. Furthermore, the clinical significance of this upregulation was validated in 174 human breast cancers. The results from human breast cancer specimens indicated that there were more VM-positive TNBC cases than those in non-TNBC cases. HIF-1a, MMP2, VE-cadherin, and Twist1 were also expressed in a higher level in human TNBC compared with non-TNBC. In aconclusion, sunitinib promoted TNBC invasion by VM. The VM status could be helpful to predict the efficacy of anti-angiogenic therapy in patients with TNBC.

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Section: Discussionmentioning

confidence: 93%

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Sun

Zhang

Yao

et al. 2017

Cancer Biology & Therapy

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“…These findings suggest a negative role for LRIG1 in regulating the EMT process of glioma cells. EMT contributes to VM formation in various tumor cells (Wang et al 2014;Du et al 2014); meanwhile, EGFR regulates EMT process through activation of the downstream effectors such as PI3K and AKT (Ye et al 2010). There exists precedent for modulating EMT through the suppression of EGFR.…”

Section: Discussionmentioning

confidence: 99%

LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells

Zhang

Song

Wei

et al. 2015

Cell Stress and Chaperones

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Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of the epidermal growth factor receptor (EGFR) signaling pathway. The aim of this study was to investigate the underlying mechanism of LRIG1 in the regulation of vasculogenic mimicry (VM) formation in glioma cells. We constructed an enhanced green fluorescent protein plasmid (pEGFP) system, pEGFP-C1-LRIG1, for overexpression of LRIG1, and transfected it into human glioma cell line SHG-44. Under hypoxic conditions induced by CoCl 2 , we investigated the effects of LRIG1 overexpression on VM formation and VM-dependent malignant behaviors including migration, invasion, and proliferation. Additionally, we explored the effects of LRIG1 on the expression levels of major components of the EGFR/PI3K/AKT pathway as well as E-cadherin and vimentin. We found that LRIG1 overexpression is able to inhibit hypoxia-induced VM formation, migration, invasion, and proliferation. Furthermore, LRIG1 overexpression counteracts hypoxiainduced increase in the expression of phosphorylated EGFR (pEGFR), PI3K (pPI3K), and AKT (pAKT) and reverts hypoxia-induced alteration in E-cadherin and vimentin expression levels. In LRIG1 knockdown SHG-44 cells, however, hypoxia-induced VM formation and alteration in E-cadherin and vimentin expression levels were exacerbated. These results suggest that the inhibitory effects of LRIG1 are most likely mediated by suppression of the EGFR/PI3K/AKT pathway and epithelial-mesenchymal transition (EMT) process. Our findings provide compelling evidence implicating LRIG1 in glioma pathophysiology, suggesting that gene therapy using LRIG1 may serve as a treatment for this disease.

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“…EMT is initiated under MACC1-indued changes, which is important for VM expansion [84]. An essential increase of EMT-connected agents, including TWIST-1 and VE-cadherin has been shown in ovarian cancer [23]. The latter agent is not the only adhesive molecule, but it may lead to induction of vascular cascade [23].…”

Section: Vasculogenic Mimicry Of Tumorsmentioning

confidence: 99%

“…An essential increase of EMT-connected agents, including TWIST-1 and VE-cadherin has been shown in ovarian cancer [23]. The latter agent is not the only adhesive molecule, but it may lead to induction of vascular cascade [23]. Earlier, Sun and co-workers [81] and Liu and co-workers [52] indicated a strong connection between EMT and VM.…”

Section: Vasculogenic Mimicry Of Tumorsmentioning

confidence: 99%

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Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

Knopik-Skrocka

Kręplewska

Jarmołowska-Jurczyszyn

2017

Advances in Cell Biology

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Summary: Blood vessel formation in tumor is defined as tumor angiogenesis. So far, the most known its mechanism is sprouting, which means formation of blood vessels from existing ones, as a result of the proliferation and migration of endothelial cells. The main mitogenic factor of these cells is vascular endothelial growth factor VEGF, acting by VEGFR-2 receptors. Recent studies have provided knowledge about the ability of tumors to form vessel-like structures. The phenomenon was called vascular mimicry. Tumor cells show a high plasticity and they can undergo differentiation to the ones with phenotype similar to endothelial cells. Each of the known tumor angiogenesis mechanisms is a result of many different factors and cell cooperation in tumor microenvironment. Tumor ability to the heterogeneous vascularization forces developing of complex, anti-angiogenic therapy directed to different molecular and cellular targets. Therapies, used so far, often lead to drug-induced hypoxia, which increases tumor cell aggressiveness and metastasis.Keywords: tumor angiogenesis, vasculogenic mimicry, anti-angiogenic strategies, resistance to anti-angiogenic therapy Sprouting angiogenesis -formation via endothelial cells proliferation and migration towards avascular tumor area of new branches of blood vessels Intussusception -formation of blood vessels as a result of intussusception (septum) inside existing blood vessels Co-option -oxygen and nutrients acquire as a result of tumor cells migration along existing blood vessels Vasculogenic mimicry -formation by tumor cells of vessel-like structures, without endothelial cells participation Vasculogenesis -formation of tumor blood vessels de novo, as a result of endothelial progenitor cells recruitment

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Hypoxia promotes vasculogenic mimicry formation by inducing epithelial–mesenchymal transition in ovarian carcinoma

Cited by 110 publications

References 27 publications

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry

LRIG1 inhibits hypoxia-induced vasculogenic mimicry formation via suppression of the EGFR/PI3K/AKT pathway and epithelial-to-mesenchymal transition in human glioma SHG-44 cells

Tumor Blood Vessels and Vasculogenic Mimicry – Current Knowledge and Searching for New Cellular/Molecular Targets of Anti-Angiogenic Therapy

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