A new perspective of vasculogenic mimicry: EMT and cancer stem cells (Review)

Fan, Yunlong; Zheng, Min; Tang, Yaling; Liang, Xin‐hua

doi:10.3892/ol.2013.1555

Cited by 120 publications

(121 citation statements)

References 111 publications

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“…Discussion VM, the ability of tumor cells to undergo vessel formation de novo, has been described in multiple cancers (reviewed in .......................................................................................................................... Fan et al 6 ). Findings from previous studies show that VM is associated with aggressive tumors and poor patient prognoses.…”

Section: Blocking Cxcr2 Receptor Signaling Impairs Proliferation and mentioning

confidence: 99%

“…[7][8][9] Indeed, a number of studies revealed that angiogenesis inhibitors did not significantly affect VM, thus underscoring the need for improved antivascular therapies that specifically target VM. 6,10,11 Transgelin (also known as SM22a and TAGLN) is an early marker of smooth muscle cell differentiation and is an actin-binding protein that affects cytoskeletal dynamics by stabilizing actin filaments. The association between transgelin and the cytoskeleton accounts for its involvement in cancer-related processes such as proliferation, migration, invasion, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…5 Maniotis et al were the first to describe VM in melanoma, and subsequent in vivo and in vitro studies reported this process in glioblastomas, breast, ovarian, and head and neck carcinomas. 5,6 VM refers to the ability of tumor cells to adopt properties of endothelial cells and form mosaic structures that can provide a blood supply for the tumor in vivo. In three-dimensional cultures in vitro, this process is recapitulated by the formation of tubular structures and patterned networks.…”

Section: Introductionmentioning

confidence: 99%

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Featured Article: Downregulation of transgelin blocks interleukin-8 utilization and suppresses vasculogenic mimicry in breast cancer cells

Aikins

Kim

Raymundo

et al. 2017

Exp Biol Med (Maywood)

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Vasculogenic mimicry (VM) is an angiogenic-independent mechanism of blood vessel formation whereby aggressive tumor cells undergo formation of capillarylike structures. Thus, interventions aimed at angiogenesis might not target the entire tumor vasculature. A more holistic approach is therefore needed in the development of improved antivascular agents.Transgelin, an actin-binding protein, has been associated with multiple stages of cancer development such as proliferation, migration and invasion, but little is known about its role in vasculogenic mimicry. We present here, an additional mechanism by which transgelin promotes malignancy by way of its association with the occurrence of VM. Although transgelin knockdown did not affect the transcript levels of most of the angiogenesis-related genes in this study, it was associated with the inhibition of the uptake of IL-8, accompanied by suppressed VM, indicating that transgelin is required for VM. These observations are relevant to the future development of efficient antivascular agents. AbstractVasculogenic mimicry (VM) is a non-classical mechanism recently described in many tumors, whereby cancer cells, rather than endothelial cells, form blood vessels. Transgelin is an actin-binding protein that has been implicated in multiple stages of cancer development. In this study, we investigated the role of transgelin in VM and assessed its effect on the expression of endothelial and angiogenesis-related genes during VM in MDA-MB-231 breast cancer cells. We confirmed the ability of MDA-MB-231 cells to undergo VM through a tube formation assay. Flow cytometry analysis revealed an increase in the expression of the endothelial-related markers VE-cadherin and CD34 in cells that underwent VM, compared with those growing in a monolayer, which was confirmed by immunocytochemistry. We employed siRNA to silence transgelin, and knockdown efficiency was determined by western blot analyses. Downregulation of transgelin suppressed cell proliferation and tube formation, but increased IL-8 levels in Matrigel cultures. RT-PCR analyses revealed that the expression of IL-8, VE-cadherin, and CD34 was unaffected by transgelin knockdown, indicating that increased IL-8 expression was not due to enhanced transcriptional activity. More importantly, the inhibition of IL-8/CXCR2 signaling also resulted in suppression of VM with increased IL-8 levels, confirming that increased IL-8 levels after transgelin knockdown was due to inhibition of IL-8 uptake. Our findings indicate that transgelin regulates VM by enhancing IL uptake. These observations are relevant to the future development of efficient antivascular agents.

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Section: Blocking Cxcr2 Receptor Signaling Impairs Proliferation and mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Featured Article: Downregulation of transgelin blocks interleukin-8 utilization and suppresses vasculogenic mimicry in breast cancer cells

Aikins

Kim

Raymundo

et al. 2017

Exp Biol Med (Maywood)

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“…The molecular mechanisms underlying VM remain unclear; nevertheless, tumor cells lining VM networks secrete matrix metalloproteinases (MMP) and express vascular endothelial (VE)-cadherin to induce extracellular matrix (ECM) remodeling (4,5). Our previous studies also showed that VM occurs in HCC (6) and that EMT may be involved in VM formation in HCC (7). Previous research data indicated that VM was observed in 18 out of 97 patients with HCC (19%; ref.…”

Section: Introductionmentioning

confidence: 96%

Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma

Meng

Sun

Zhao

et al. 2014

Molecular Cancer Therapeutics

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This study was conducted to examine the effects of doxycycline on the survival time and proliferation of hepatocellular carcinoma (HCC) in vivo and on the biologic functions of HCC in vitro. This study was also designed to evaluate the effects of doxycycline on epithelial-to-mesenchymal transition (EMT)-and vasculogenic mimicry (VM)-related protein expression and on matrix metalloproteinase (MMP) and DNA methyltransferase (DNMT) activity in vitro. Human MHCC97H cells were injected into BALB/c mice, which were divided into treatment and control groups. Doxycycline treatment prolonged the mouse survival time and partly suppressed the growth of engrafted HCC tumor cells, with an inhibition rate of 43.39%. Higher amounts of VM and endothelium-dependent vessels were found in the control group than the treatment group. IHC indicated that epithelial (E)-cadherin expression was increased in the doxycycline-treated mice compared with the control group. In in vitro experiments, doxycycline promoted HCC cell adhesion but inhibited HCC cell viability, proliferation, migration, and invasion. Western blot analysis, semiquantitative RT-PCR, qRT-PCR, and immunofluorescence demonstrated that doxycycline inhibited the degradation of the epithelial marker E-cadherin and downregulated the expression levels of EMT promoters, the mesenchymal marker vimentin, and the VM-associated marker vascular endothelial (VE)-cadherin. Furthermore, the activities of MMPs and DNMTs were examined in different groups via gelatin zymography and a DNMT activity assay kit. A methylation-specific PCR was performed to assess the promoter methylation of CDH1 (the gene encoding E-cadherin). Doxycycline prolonged the mouse survival time by inhibiting EMT progression and VM formation. Mol Cancer Ther; 13(12); 3107-22. Ó2014 AACR.

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“…The epithelial-mesenchymal transition (EMT) is a process implicated in drug resistance, metastasis and the generation of CSCs (21,31,32). The present study analyzed the mRNA and protein expression of the EMT markers E-cadherin and N-cadherin in pancreatic cancer cells treated with thalidomide.…”

Section: Discussionmentioning

confidence: 99%

Thalidomide inhibits proliferation and epithelial‑mesenchymal transition by modulating CD133 expression in pancreatic cancer cells

Chen

Xiao

et al. 2017

Oncol Lett

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Abstract. Pancreatic cancer is a solid malignancy with a high mortality rate, on account of the high incidence of metastasis at the time of detection. The aggressiveness of pancreatic cancer may be partly driven by cancer stem cells (CSCs), which are characterized by the ability to self-renew and recapitulate tumors in the ectopic setting. However, although a number of drugs targeting CSCs are currently under clinical investigation, few effective drugs have been developed. The present study demonstrated that thalidomide inhibited cell proliferation and metastasis in pancreatic cancer cell lines through the inhibition of epithelial mesenchymal transition. The effect of thalidomide was more pronounced in cluster of differentiation 133 (CD133) + SW1990 cells than in Capan-2 cells, in which CD133 expression was almost undetectable. The results revealed that CD133 is likely to serve a role in the antitumor effect of thalidomide and indicated that thalidomide could be developed as a CSC-specific adjuvant chemotherapy in pancreatic cancer. IntroductionPancreatic cancer is a disease with a high mortality rate that is characterized by the early metastasis to local and distant organs; the majority of patients present with unresectable disease at the time of initial diagnosis (1). Therefore, patients with pancreatic cancer have a poor prognosis, with an overall 5-year survival rate of <5% in the United States between 1975 and 2008 (2). No significant advances in the treatment of pancreatic cancer have been made in >10 years, largely due to of the resistance of the disease to conventional chemotherapy and radiation therapy (3-6). The involvement of cancer stem cells (CSC; also termed tumor-initiating cells) in the development of chemotherapy resistance has been reported in a number of types of malignancy (7-9). CSCs are a phenotypically distinct population of cells that are functionally defined by their ability to form tumors, self-renew and differentiate, as well as their resistance to chemotherapy (10,11). Therefore, the development of novel chemotherapeutic agents that are effective against CSCs is urgently required.Thalidomide is a non-barbiturate sedative and hypnotic drug with anti-angiogenic and immunomodulatory properties (12). Thalidomide is currently used in the treatment of various types of malignant tumor, including prostate cancer (13), glioblastoma (14), glioma (15), renal cell carcinoma (16) and advanced breast cancer (17). The mechanism of action of thalidomide includes the inhibition of vascular endothelial growth factor, basic fibroblast growth factor and tumor necrosis factor-α, the inhibition of angiogenesis, and the stimulation of natural killer cells (12). However, to the best of our knowledge, the use of thalidomide in the treatment of pancreatic cancer has not been assessed and the potential mechanism of thalidomide-mediated inhibition of tumor cell viability remains to be elucidated. In the present study, the effect of thalidomide on pancreatic cancer cells was examined, alongside its mechanism of ...

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A new perspective of vasculogenic mimicry: EMT and cancer stem cells (Review)

Cited by 120 publications

References 111 publications

Featured Article: Downregulation of transgelin blocks interleukin-8 utilization and suppresses vasculogenic mimicry in breast cancer cells

Featured Article: Downregulation of transgelin blocks interleukin-8 utilization and suppresses vasculogenic mimicry in breast cancer cells

Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma

Thalidomide inhibits proliferation and epithelial‑mesenchymal transition by modulating CD133 expression in pancreatic cancer cells

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