IL-33/ST2 Axis Regulates Vasculogenic Mimicry via ERK1/2-MMP-2/9 Pathway in Melanoma

Dermatology ◽  
2019 ◽  
Vol 235 (3) ◽  
pp. 225-233 ◽  
Author(s):  
Fuhan Yang ◽  
Mingming Wen ◽  
Dayu Pan ◽  
Xian Lin ◽  
Jing Mo ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Vasculogenic Mimicry ◽  
Melanoma Cells ◽  
Tube Formation ◽  
Migration And Invasion ◽  
Rapid Progression ◽  
Inflammatory Factor ◽  
Action Methods ◽  
Significant Health

Background: Melanoma, an extremely malignant form of cancer, poses a significant health risk. Vasculogenic mimicry (VM), blood vessels formed by tumor cells instead of endothelial cells, is an important factor for the rapid progression of melanoma. Interleukin (IL)-33 is an inflammatory factor commonly found in the tumor microenvironment and plays an important role in the progression of many tumors. IL-33 acts on immune cells and tumor cells through its receptor ST2. This study hypothesized that IL-33 directly affects the progression of melanoma. Objectives: This study was designed to investigate the effect of IL-33 on VM of melanoma and its potential mechanism of action. Methods: The expression of ST2 was evaluated in 66 cases of melanoma collected from human patients, and the differences were analyzed. In vitro experiments were conducted to study the effects of the IL-33/ST2 axis on cell migration and invasion and to elucidate possible mechanisms. Results: ST2 expression is associated with that of matrix metalloproteinase (MMP)-2 and VM in melanoma of patients. IL-33 increases the abilities of proliferation, migration and invasion of melanoma cells and VM tube formation through ST2. IL-33 induces the production of MMP-2/9 via ERK1/2 phosphorylation. Conclusion: IL-33 can directly act on melanoma cells and promote its development.

scholarly journals uPAR controls vasculogenic mimicry ability expressed by drug-resistant melanoma cells

2021 ◽  
Author(s):  
Elena Andreucci ◽  
Anna Laurenzana ◽  
Silvia Peppicelli ◽  
Alessio Biagioni ◽  
Francesca Margheri ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Vasculogenic Mimicry ◽  
Melanoma Cells ◽  
Experimental Models ◽  
Rapid Progression ◽  
Drug Resistant ◽  
Urokinase Plasminogen Activator Receptor ◽  
Tumor Spread ◽  
Tumor Dissemination

Malignant melanoma is a highly aggressive skin cancer characterized by an elevated grade of tumor cell plasticity. Such plasticity allows melanoma cells adaptation to different hostile conditions and guarantees tumor survival and disease progression, including aggressive features such as drug resistance. Indeed, almost 50% of melanoma rapidly develop resistance to the BRAFV600E inhibitor vemurafenib, with fast tumor dissemination, a devastating consequence for patients' outcomes. Vasculogenic mimicry (VM), the ability of cancer cells to organize themselves in perfused vascular-like channels, might sustain tumor spread by providing vemurafenib-resistant cancer cells with supplementary ways to enter into circulation and disseminate. Thus, this research aims to determine if vemurafenib resistance goes with the acquisition of VM ability by aggressive melanoma cells, and identify a driving molecule for both vemurafenib resistance and VM. We used two independent experimental models of drug-resistant melanoma cells, the first one represented by a chronic adaptation of melanoma cells to extracellular acidosis, known to drive a particularly aggressive and vemurafenib-resistant phenotype, the second one generated with chronic vemurafenib exposure. By performing in vitro tube formation assay and evaluating the expression levels of the VM markers EphA2 and VE-cadherin by western blotting and flow cytometer analyses, we demonstrated that vemurafenib-resistant cells obtained by both models are characterized by an increased ability to perform VM. Moreover, by exploiting the CRISPR-Cas9 technique and using the urokinase plasminogen activator receptor (uPAR) inhibitor M25, we identified uPAR as a driver of VM expressed by vemurafenib-resistant melanoma cells. Thus, uPAR targeting may be successfully leveraged as a new complementary therapy to inhibit VM in drug-resistant melanoma patients, to counteract the rapid progression and dissemination of the disease.

scholarly journals SOCS1 favors the epithelial-mesenchymal transition in melanoma, promotes tumor progression and prevents antitumor immunity by PD-L1 expression

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
R. Berzaghi ◽  
V. S. C. Maia ◽  
F. V. Pereira ◽  
F. M. Melo ◽  
M. S. Guedes ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tumor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Tumor Development ◽  
Growth Factor Receptor ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
Fibroblast Growth Factor Receptors ◽  
Mesenchymal Transition

Abstract Silencing of SOCS1 protein with shRNAi lentivirus (shR-SOCS1) led to partial reversion of the tumorigenic phenotype of B16F10-Nex2 melanoma cells. SOCS1 silencing inhibited cell migration and invasion as well as in vitro growth by cell cycle arrest at S phase with increased cell size and nuclei. Down-regulation of SOCS1 decreased the expression of epidermal growth factor receptor, Ins-Rα, and fibroblast growth factor receptors. The present work aimed at analyzing the SOCS1 cell signaling and expression of proteins relevant to tumor development. An RNA microarray analysis of B16F10-Nex2 melanoma cells with SOCS1 silenced by shRNAi-SOCS1 was undertaken in comparison with cells transduced with the empty vector. Among 609 differentially expressed genes, c-Kit, Met and EphA3 cytokine/tyrosine-kinase (TK) receptors were down regulated. A significant decrease in the expression of TK receptors, the phosphorylation of mediators of ERK1/2 and p38 pathways and STAT3 (S727) were observed. Subcutaneous immunization with shR-SOCS1-transduced viable tumor cells rendered protection against melanoma in a syngeneic model, with decreased expression of PD-L1 and of matrix metallo-proteinases (MMPs) and CD-10 in those cells. The present work shows the role of SOCS1 in murine melanoma development and the potential of SOCS1-silenced tumor cells in raising an effective anti-melanoma immune response.

scholarly journals INCREASED LEVEL OF MIR-204-5P EXPRESSION IN MELANOMA CELLS UNDER THE INFLUENCE OF DACARBAZINE

2019 ◽  
Vol 18 (3) ◽  
pp. 45-53
Author(s):  
S. N. Lavrentiev ◽  
M. B. Aksenenko ◽  
A. S. Averchuk ◽  
A. V. Komina ◽  
N. V. Palkina ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Animal Behavior ◽  
Growth Dynamics ◽  
Inhibitory Effect ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Metastasis Development

Various types of tissues was analyzed, and the algorithm for summing neutron and photon doses in neutronMiRNA s are involved in the regulation of numerous critical biological processes, including cell proliferation, differentiation, migration and invasion. They function as oncogenes or tumor suppressors according to the nature of the target. It has been previously determined that miR-204-5p miRNA is characterized by the increased level in melanoma. The aim of this study was to determine the effects of changes in the level of microRNA expression when dacarbazine was exposed to melanoma cells in vitro and synthetic miR-204-5p in vivo. The expression levels of miR-204-5p and miR-211 in melanoma cells were determined by real-time PCR. Antitumor effects in vivo were verified in assessing the growth dynamics of the tumor node. Toxic effects were assessed by animal behavior, fluid intake, feed, and ALT , AST , creatinine, urea levels. In the model of melanoma C57BL6, it was revealed that the introduction of the synthetic miR-204-5p did not cause significant changes in the investigated microRNA in tumor cells. At the same time, the antitumor effects of dacarbazine in melanoma cells in vitro led to an increase in the level of the investigated microRNA by more than 20 times. The results of the study indicated the possibility of compensating the level of miR-204-5p under the influence of cytostatic therapy. Taking into account the previously revealed miR-204-5p inhibitory effect on the proliferation of melanoma cells, we can assume that this miRNA can play a role in maintaining the dermal state of tumor cells. Further studies are required to understand the metastasis development and predict the response to antitumor therapy for melanoma.

scholarly journals Histone Deacetylase Inhibitors Impair Vasculogenic Mimicry from Glioblastoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 747 ◽  
Author(s):  
Olga Pastorino ◽  
Maria Teresa Gentile ◽  
Alessandro Mancini ◽  
Nunzio Del Gaudio ◽  
Antonella Di Costanzo ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Trichostatin A ◽  
Treatment Options ◽  
Vasculogenic Mimicry ◽  
Tube Formation ◽  
Migration And Invasion ◽  
Who Grade ◽  
Rat Glioma

Glioblastoma (GBM), a high-grade glioma (WHO grade IV), is the most aggressive form of brain cancer. Available treatment options for GBM involve a combination of surgery, radiation and chemotherapy but result in a poor survival outcome. GBM is a high-vascularized tumor and antiangiogenic drugs are widely used in GBM therapy as adjuvants to control abnormal vasculature. Vasculogenic mimicry occurs in GBM as an alternative vascularization mechanism, providing a means whereby GBM can escape anti-angiogenic therapies. Here, using an in vitro tube formation assay on Matrigel®, we evaluated the ability of different histone deacetylase inhibitors (HDACis) to interfere with vasculogenic mimicry. We found that vorinostat (SAHA) and MC1568 inhibit tube formation by rat glioma C6 cells. Moreover, at sublethal doses for GBM cells, SAHA, trichostatin A (TSA), entinostat (MS275), and MC1568 significantly decrease tube formation by U87MG and by patient-derived human GBM cancer stem cells (CSCs). The reduced migration and invasion of HDACis-treated U87 cells, at least in part, may account for the inhibition of tube formation. In conclusion, our results indicate that HDACis are promising candidates for blocking vascular mimicry in GBM.

scholarly journals N6-Isopentenyladenosine Hinders the Vasculogenic Mimicry in Human Glioblastoma Cells through Src-120 Catenin Pathway Modulation and RhoA Activity Inhibition

2021 ◽  
Vol 22 (19) ◽  
pp. 10530
Author(s):  
Cristina Pagano ◽  
Giovanna Navarra ◽  
Olga Pastorino ◽  
Giorgio Avilia ◽  
Laura Coppola ◽  
...  
Keyword(s):  
Vasculogenic Mimicry ◽  
Tube Formation ◽  
Migration And Invasion ◽  
Dependent Manner ◽  
P120 Catenin ◽  
Rhoa Activity ◽  
Rhoa Gtpase ◽  
Human Gbm ◽  
Effective Drugs

Background: Vasculogenic mimicry (VM) is a functional microcirculation pattern formed by aggressive tumor cells. Thus far, no effective drugs have been developed to target VM. Glioblastoma (GBM) is the most malignant form of brain cancer and is a highly vascularized tumor. Vasculogenic mimicry represents a means whereby GBM can escape anti-angiogenic therapies. Methods: Here, using an in vitro tube formation assay on Matrigel, we evaluated the ability of N6-isopentenyladenosine (iPA) to interfere with vasculogenic mimicry (VM). RhoA activity was assessed using a pull-down assay, while the modulation of the adherens junctions proteins was analyzed by Western blot analysis. Results: We found that iPA at sublethal doses inhibited the formation of capillary-like structures suppressing cell migration and invasion of U87MG, U343MG, and U251MG cells, of patient-derived human GBM cells and GBM stem cells. iPA reduces the vascular endothelial cadherin (VE-cadherin) expression levels in a dose-dependent manner, impairs the vasculogenic mimicry network by modulation of the Src/p120-catenin pathway and inhibition of RhoA-GTPase activity. Conclusions: Taken together, our results revealed iPA as a promising novel anti-VM drug in GBM clinical therapeutics.

scholarly journals The cancer glycocalyx mediates intravascular adhesion and extravasation during metastatic dissemination

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Giovanni S. Offeddu ◽  
Cynthia Hajal ◽  
Colleen R. Foley ◽  
Zhengpeng Wan ◽  
Lina Ibrahim ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Tumor Cells ◽  
Cancer Progression ◽  
Vascular System ◽  
Migration And Invasion ◽  
Improve Patient Survival ◽  
Adhesive Interactions ◽  
Vitro Model ◽  
Metastatic Sites

AbstractThe glycocalyx on tumor cells has been recently identified as an important driver for cancer progression, possibly providing critical opportunities for treatment. Metastasis, in particular, is often the limiting step in the survival to cancer, yet our understanding of how tumor cells escape the vascular system to initiate metastatic sites remains limited. Using an in vitro model of the human microvasculature, we assess here the importance of the tumor and vascular glycocalyces during tumor cell extravasation. Through selective manipulation of individual components of the glycocalyx, we reveal a mechanism whereby tumor cells prepare an adhesive vascular niche by depositing components of the glycocalyx along the endothelium. Accumulated hyaluronic acid shed by tumor cells subsequently mediates adhesion to the endothelium via the glycoprotein CD44. Trans-endothelial migration and invasion into the stroma occurs through binding of the isoform CD44v to components of the sub-endothelial extra-cellular matrix. Targeting of the hyaluronic acid-CD44 glycocalyx complex results in significant reduction in the extravasation of tumor cells. These studies provide evidence of tumor cells repurposing the glycocalyx to promote adhesive interactions leading to cancer progression. Such glycocalyx-mediated mechanisms may be therapeutically targeted to hinder metastasis and improve patient survival.

scholarly journals CD36 promotes vasculogenic mimicry in melanoma by mediating adhesion to the extracellular matrix

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Carmela Martini ◽  
Mark DeNichilo ◽  
Danielle P. King ◽  
Michaelia P. Cockshell ◽  
Brenton Ebert ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Vasculogenic Mimicry ◽  
Tumor Vasculature ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Cell Surface Glycoprotein ◽  
Melanoma Cancer ◽  
In Vitro Angiogenesis

Abstract Background The formation of blood vessels within solid tumors directly contributes to cancer growth and metastasis. Until recently, tumor vasculature was thought to occur exclusively via endothelial cell (EC) lined structures (i.e. angiogenesis), but a second source of tumor vasculature arises from the cancer cells themselves, a process known as vasculogenic mimicry (VM). While it is generally understood that the function of VM vessels is the same as that of EC-lined vessels (i.e. to supply oxygen and nutrients to the proliferating cancer cells), the molecular mechanisms underpinning VM are yet to be fully elucidated. Methods Human VM-competent melanoma cell lines were examined for their VM potential using the in vitro angiogenesis assays (Matrigel), together with inhibition studies using small interfering RNA and blocking monoclonal antibodies. Invasion assays and adhesion assays were used to examine cancer cell function. Results Herein we demonstrate that CD36, a cell surface glycoprotein known to promote angiogenesis by ECs, also supports VM formation by human melanoma cancer cells. In silico analysis of CD36 expression within the melanoma cohort of The Cancer Genome Atlas suggests that melanoma patients with high expression of CD36 have a poorer clinical outcome. Using in vitro ‘angiogenesis’ assays and CD36-knockdown approaches, we reveal that CD36 supports VM formation by human melanoma cells as well as adhesion to, and invasion through, a cancer derived extracellular matrix substrate. Interestingly, thrombospondin-1 (TSP-1), a ligand for CD36 on ECs that inhibits angiogenesis, has no effect on VM formation. Further investigation revealed a role for laminin, but not collagen or fibronectin, as ligands for CD36 expressing melanoma cells. Conclusions Taken together, this study suggests that CD36 is a novel regulator of VM by melanoma cancer cells that is facilitated, at least in part, via integrin-α3 and laminin. Unlike angiogenesis, VM is not perturbed by the presence of TSP-1, thus providing new information on differences between these two processes of tumor vascularization which may be exploited to combat cancer progression.

Luteolin inhibits the proliferation, adhesion, migration and invasion of choroidal melanoma cells in vitro

2021 ◽  
pp. 108643
Author(s):  
Meng-Lin Shi ◽  
Yu-Fen Chen ◽  
Wei-Qi Wu ◽  
Yao Lai ◽  
Qi Jin ◽  
...  
Keyword(s):  
Choroidal Melanoma ◽  
Melanoma Cells ◽  
Migration And Invasion

8-Formylophiopogonanone B induces ROS-mediated apoptosis in nasopharyngeal carcinoma CNE-1 cells

2021 ◽  
Author(s):  
Ya-jing Zhang ◽  
Zhen-lin Mu ◽  
Ping Deng ◽  
Yi-dan Liang ◽  
Li-chuan Wu ◽  
...  
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Cell Viability ◽  
Tumor Cells ◽  
High Efficiency ◽  
Pharmacological Action ◽  
Migration And Invasion ◽  
Ros Production ◽  
Biological Functions ◽  
Intracellular Ros

Abstract Cancer is one of the leading causes of death in the world. It is very important to find drugs with high efficiency, low toxicity, and low side effects for the treatment of cancer. Flavonoids and their derivatives with broad biological functions have been recognized as anti-tumor chemicals. 8-Formylophiopogonanone B (8-FOB), a naturally existed homoisoflavonoids with rarely known biological functions, needs pharmacological evaluation. In order to explore the possible anti-tumor action of 8-FOB, we used six types of tumor cells to evaluate in vitro effects of this agent on cell viability and tested the effects on clone formation ability, scratching wound-healing, and apoptosis. In an attempt to elucidate the mechanism of pharmacological action, we examined 8-FOB-induced intracellular oxidative stress and -disrupted mitochondrial function. Results suggested that 8-FOB could suppress tumor cell viability, inhibit cell migration and invasion, induce apoptosis, and elicit intracellular ROS production. Among these six types of tumor cells, the nasopharyngeal carcinoma CNE-1 cells were the most sensitive cancer cells to 8-FOB treatment. Intracellular ROS production played a pivotal role in the anti-tumor action of 8-FOB. Our present study is the first to document that 8-FOB has anti-tumor activity in vitro and increases intracellular ROS production, which might be responsible for its anti-tumor action. The anti-tumor pharmacological effect of 8-FOB is worthy of further investigation.

scholarly journals MicroRNA-27a-5p inhibits proliferation, migration and invasion and promotes apoptosis of Wilms tumor cell by targeting PBOV1

2021 ◽  
Author(s):  
zhengtuan guo ◽  
qiang yv ◽  
chunlin miao ◽  
wenan ge ◽  
peng li
Keyword(s):  
Tumor Cells ◽  
Wilms Tumor ◽  
Suppressive Effect ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Tumor Tissues ◽  
And Function ◽  
Tumor Suppressive Effect

Wilms tumor is the most common type of renal tumor in children. MicroRNAs (miRNA) are small non-coding RNAs that play crucial regulatory roles in tumorigenesis. We aimed to study the expression profile and function of miR-27a-5p in Wilms tumor. MiR-27a-5p expression was downregulated in human Wilms tumor tissues. Functionally, overexpression of miR-27a-5p promoted cell apoptosis of Wilms tumor cells. Furthermore, upregulated miR-27a-5p delayed xenograft Wilms tumor tumorigenesis in vivo. Bioinformatics analysis predicted miR-27-5p directly targeted to the 3’-untranslated region (UTR) of PBOV1 and luciferase reporter assay confirmed the interaction between miR-27a-5p and PBOV1. The function of PBOV1 in Wilms tumor was evaluated in vitro and knockdown of PBOV1 dampened cell migration. In addition, overexpression of PBOV1 antagonized the tumor-suppressive effect of miR-27a-5p in Wilms tumor cells. Collectively, our findings reveal the regulatory axis of miR-27-5p/PBOV1 in Wilms tumor and miR-27a-5p might serve as a novel therapeutic target in Wilms tumor.

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