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.

scholarly journals CD36 Promotes Vasculogenic Mimicry in Melanoma by Mediating Adhesion to the Extracellular Matrix

2021 ◽  
Author(s):  
Carmela Martini ◽  
Mark DeNichilo ◽  
Danielle P. King ◽  
Michaelia P. Cockshell ◽  
Brenton Ebert ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Vasculogenic Mimicry ◽  
Tumor Vasculature ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Cell Surface Glycoprotein ◽  
Melanoma Cancer

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-a3 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.

scholarly journals Capsaicin Exerts Therapeutic Effects by targeting tNOX-SIRT1 Axis and Augmenting ROS-Dependent Cytotoxic Autophagy in Melanoma Cancer Cells

2020 ◽  
Author(s):  
Atikul Islam ◽  
Pei-Fang Hsieh ◽  
Jou-Chun Chou ◽  
Jiunn-Wang Liao ◽  
Ming-Kun Hsieh ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Cancer Cells ◽  
Nadh Oxidase ◽  
Treatment Options ◽  
Melanoma Cells ◽  
Therapeutic Effects ◽  
Melanoma Cancer ◽  
Anticancer Properties

Abstract Background: Although considered a rare form of skin cancer, malignant melanoma has steadily increased internationally and is a main cause of cancer-associated death worldwide. The treatment options for malignant melanoma are very limited. Accumulating data suggest that the natural compound, capsaicin, exhibits preferential anticancer properties to act as a nutraceutical agent. Here, we explored the underlying molecular events involved in the inhibitory effects of capsaicin on the growth of melanoma cells.Methods: The cellular thermal shift assay (CETSA) and isothermal dose response fingerprint (ITDRFCETSA) were utilized to validate the binding of capsaicin with the tumor-associated NADH oxidase, tNOX (ENOX2) in melanoma cells. We also assessed the cellular impact of capsaicin-targeting of tNOX on A375 cells by flow cytometry and protein analysis. The essential role of tNOX in tumor- and melanoma-growth limiting abilities of capsaicin was evaluated in C57BL/6 mice.Results: Our data show that capsaicin directly targets cellular tNOX to inhibit its enzymatic activity and enhance protein degradation capacity. The inhibition of tNOX by capsaicin is accompanied by the attenuation of SIRT1, a NAD+-dependent deacetylase that enhances ULK1 acetylation to induce ROS-dependent autophagy in melanoma cells. Capsaicin treatment of mice implanted with melanoma cancer cells suppressed tumor growth by down-regulating tNOX and SIRT1, which was also seen in an in vivo xenograft study with tNOX-depleted melanoma cells. Conclusions: Together, our findings suggest that tNOX expression is important for the growth of melanoma cancer cells both in vitro and in vivo, and that inhibition of the tNOX-SIRT1 axis contributes to inducting cytotoxic ROS-dependent autophagy in melanoma cells.

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 Inhibitory Effect of Melanoma Differentiation Associated Gene-7/Interleukin-24 on Invasion In Vitro of Human Melanoma Cancer Cells

2013 ◽  
Vol 28 (6) ◽  
pp. 833 ◽  
Author(s):  
Bi-wen Lin ◽  
Ze-long Jiao ◽  
Jian-feng Fan ◽  
Liang Peng ◽  
Lei Li ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Inhibitory Effect ◽  
Human Melanoma ◽  
Melanoma Cancer

scholarly journals Vascular Channel Formation by Human Melanoma Cells in Vivo and in Vitro: Vasculogenic Mimicry

1999 ◽  
Vol 155 (3) ◽  
pp. 739-752 ◽  
Author(s):  
Andrew J. Maniotis ◽  
Robert Folberg ◽  
Angela Hess ◽  
Elisabeth A. Seftor ◽  
Lynn M.G. Gardner ◽  
...  
Keyword(s):  
Vasculogenic Mimicry ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Channel Formation ◽  
Vascular Channel ◽  
Human Melanoma Cells

scholarly journals Cyclic AMP Signaling as a Mediator of Vasculogenic Mimicry in Aggressive Human Melanoma Cells In vitro

2009 ◽  
Vol 69 (3) ◽  
pp. 802-809 ◽  
Author(s):  
Jean-Claude Lissitzky ◽  
Danielle Parriaux ◽  
Elodie Ristorcelli ◽  
Alain Vérine ◽  
Dominique Lombardo ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Vasculogenic Mimicry ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cells ◽  
Cyclic Amp Signaling

scholarly journals Computational Methods for Structure-to-Function Analysis of Diet-Derived Catechins-Mediated Targeting of In Vitro Vasculogenic Mimicry

2021 ◽  
Vol 20 ◽  
pp. 117693512110092
Author(s):  
Abicumaran Uthamacumaran ◽  
Narjara Gonzalez Suarez ◽  
Abdoulaye Baniré Diallo ◽  
Borhane Annabi
Keyword(s):  
Machine Learning ◽  
Cancer Cells ◽  
Structural Changes ◽  
Function Analysis ◽  
Vasculogenic Mimicry ◽  
Machine Learning Algorithms ◽  
Emergent Behavior ◽  
Molecular Signature ◽  
Ovarian Cancer Cells

Background: Vasculogenic mimicry (VM) is an adaptive biological phenomenon wherein cancer cells spontaneously self-organize into 3-dimensional (3D) branching network structures. This emergent behavior is considered central in promoting an invasive, metastatic, and therapy resistance molecular signature to cancer cells. The quantitative analysis of such complex phenotypic systems could require the use of computational approaches including machine learning algorithms originating from complexity science. Procedures: In vitro 3D VM was performed with SKOV3 and ES2 ovarian cancer cells cultured on Matrigel. Diet-derived catechins disruption of VM was monitored at 24 hours with pictures taken with an inverted microscope. Three computational algorithms for complex feature extraction relevant for 3D VM, including 2D wavelet analysis, fractal dimension, and percolation clustering scores were assessed coupled with machine learning classifiers. Results: These algorithms demonstrated the structure-to-function galloyl moiety impact on VM for each of the gallated catechin tested, and shown applicable in quantifying the drug-mediated structural changes in VM processes. Conclusions: Our study provides evidence of how appropriate 3D VM compression and feature extractors coupled with classification/regression methods could be efficient to study in vitro drug-induced perturbation of complex processes. Such approaches could be exploited in the development and characterization of drugs targeting VM.

scholarly journals Mitochondrial function is controlled by melatonin and its metabolites in vitro in human melanoma cells

2021 ◽  
Vol 70 (3) ◽  
Author(s):  
Bernadetta Bilska ◽  
Fiona Schedel ◽  
Anna Piotrowska ◽  
Joanna Stefan ◽  
Michal Zmijewski ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cells

scholarly journals The phosphatase Shp1 interacts with and dephosphorylates cortactin to inhibit invadopodia function

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Alessia Varone ◽  
Chiara Amoruso ◽  
Marcello Monti ◽  
Manpreet Patheja ◽  
Adelaide Greco ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tyrosine Phosphatase ◽  
Melanoma Cells ◽  
Matrix Degradation ◽  
Extracellular Matrix Degradation ◽  
Invadopodia Formation ◽  
Interference Rna

Abstract Background Invadopodia are actin-based cell-membrane protrusions associated with the extracellular matrix degradation accompanying cancer invasion. The elucidation of the molecular mechanisms leading to invadopodia formation and activity is central for the prevention of tumor spreading and growth. Protein tyrosine kinases such as Src are known to regulate invadopodia assembly, little is however known on the role of protein tyrosine phosphatases in this process. Among these enzymes, we have selected the tyrosine phosphatase Shp1 to investigate its potential role in invadopodia assembly, due to its involvement in cancer development. Methods Co-immunoprecipitation and immunofluorescence studies were employed to identify novel substrate/s of Shp1AQ controlling invadopodia activity. The phosphorylation level of cortactin, the Shp1 substrate identified in this study, was assessed by immunoprecipitation, in vitro phosphatase and western blot assays. Short interference RNA and a catalytically-dead mutant of Shp1 expressed in A375MM melanoma cells were used to evaluate the role of the specific Shp1-mediated dephosphorylation of cortactin. The anti-invasive proprieties of glycerophosphoinositol, that directly binds and regulates Shp1, were investigated by extracellular matrix degradation assays and in vivo mouse model of metastasis. Results The data show that Shp1 was recruited to invadopodia and promoted the dephosphorylation of cortactin at tyrosine 421, leading to an attenuated capacity of melanoma cancer cells to degrade the extracellular matrix. Controls included the use of short interference RNA and catalytically-dead mutant that prevented the dephosphorylation of cortactin and hence the decrease the extracellular matrix degradation by melanoma cells. In addition, the phosphoinositide metabolite glycerophosphoinositol facilitated the localization of Shp1 at invadopodia hence promoting cortactin dephosphorylation. This impaired invadopodia function and tumor dissemination both in vitro and in an in vivo model of melanomas. Conclusion The main finding here reported is that cortactin is a specific substrate of the tyrosine phosphatase Shp1 and that its phosphorylation/dephosphorylation affects invadopodia formation and, as a consequence, the ability of melanoma cells to invade the extracellular matrix. Shp1 can thus be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs.

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