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Article: Vasculogenic Mimicry: Become an Endothelial Cell "But Not So Much".

Fernández-Cortés, Mónica / Delgado-Bellido, Daniel / Oliver, F Javier

2019 Volume 9, Page(s) 803

Abstract: Blood vessels supply all body tissues with nutrients and oxygen, take away waste products and allow the arrival of immune cells and other cells (pericytes, smooth muscle cells) that form part of these vessels around the principal endothelial cells. ... ...

Abstract	Blood vessels supply all body tissues with nutrients and oxygen, take away waste products and allow the arrival of immune cells and other cells (pericytes, smooth muscle cells) that form part of these vessels around the principal endothelial cells. Vasculogenic mimicry (VM) is a tumor blood supply system that takes place independently of angiogenesis or endothelial cells, and is associated with poor survival in cancer patients. Aberrant expression of VE-cadherin has been strongly associated with VM. Even more, VE-cadherin has constitutively high phosphorylation levels on the residue of Y658 in human malignant melanoma cells. In this review we focus on non-endothelial VE-cadherin and its post-translational modifications as a crucial component in the development of tumor VM, highlighting the signaling pathways that lead to their pseudo-endothelial and stem-like phenotype and the role of tumor microenvironment. We discuss the importance of the tumor microenvironment in VM acquisition, and describe the most recent therapeutic targets that have been proposed for the repression of VM.
Language	English
Publishing date	2019-08-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00803
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Article ; Online: PARP inhibition promotes endothelial-like traits in melanoma cells and modulates pericyte coverage dynamics during vasculogenic mimicry.

Fernández-Cortés, Mónica / Delgado-Bellido, Daniel / Bermúdez-Jiménez, Eloísa / Paramio, Jesús M / O'Valle, Francisco / Vinckier, Stefan / Carmeliet, Peter / Garcia-Diaz, Angel / Oliver, F Javier

The Journal of pathology

2023 Volume 259, Issue 3, Page(s) 318–330

Abstract: Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 is implicated in the activation of hypoxia-inducible factors, which are crucial in ...

Abstract	Vasculogenic mimicry (VM) describes the ability of highly aggressive tumor cells to develop pseudovascular structures without the participation of endothelial cells. PARP1 is implicated in the activation of hypoxia-inducible factors, which are crucial in tumor neovascularization. We have explored the role of hypoxia and PARP inhibition in VM. In uveal melanoma xenografts, the PARP inhibitor olaparib improved in vivo pericyte coverage specifically of VM channels. This was concomitant with reduced metastasis in olaparib-treated VM
MeSH term(s)	Humans ; Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Endothelial Cells/metabolism ; Pericytes/metabolism ; Melanoma/drug therapy ; Melanoma/metabolism ; Neovascularization, Pathologic/pathology ; Phenotype ; Cell Line, Tumor
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2023-01-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6043
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Article ; Online: Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities.

Zamudio-Martinez, Esteban / Herrera-Campos, Ana Belén / Muñoz, Alberto / Rodríguez-Vargas, José Manuel / Oliver, F Javier

Journal of experimental & clinical cancer research : CR

2021 Volume 40, Issue 1, Page(s) 144

Abstract: Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins that are gaining increasing importance due to their implication in multiple pathways and diseases such as cancer. TNKS1/2 interact with a large variety of substrates through the ... ...

Abstract	Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins that are gaining increasing importance due to their implication in multiple pathways and diseases such as cancer. TNKS1/2 interact with a large variety of substrates through the ankyrin (ANK) domain, which recognizes a sequence present in all the substrates of tankyrase, called Tankyrase Binding Motif (TBM). One of the main functions of tankyrases is the regulation of protein stability through the process of PARylation-dependent ubiquitination (PARdU). Nonetheless, there are other functions less studied that are also essential in order to understand the role of tankyrases in many pathways. In this review, we concentrate in different tankyrase substrates and we analyze in depth the biological consequences derived of their interaction with TNKS1/2. We also examine the concept of both canonical and non-canonical TBMs and finally, we focus on the information about the role of TNKS1/2 in different tumor context, along with the benefits and limitations of the current TNKS inhibitors targeting the catalytic PARP domain and the novel strategies to develop inhibitors against the ankyrin domain. Available data indicates the need for further deepening in the knowledge of tankyrases to elucidate and improve the current view of the role of these PARP family members and get inhibitors with a better therapeutic and safety profile.
MeSH term(s)	Humans ; Neoplasms/therapy ; Tankyrases/metabolism
Chemical Substances	Tankyrases (EC 2.4.2.30)
Language	English
Publishing date	2021-04-28
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	803138-1
ISSN	1756-9966 ; 0392-9078
ISSN (online)	1756-9966
ISSN	0392-9078
DOI	10.1186/s13046-021-01950-6
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Article: Implications of Hyperoxia over the Tumor Microenvironment: An Overview Highlighting the Importance of the Immune System.

Herrera-Campos, Ana Belén / Zamudio-Martinez, Esteban / Delgado-Bellido, Daniel / Fernández-Cortés, Mónica / Montuenga, Luis M / Oliver, F Javier / Garcia-Diaz, Angel

Cancers

2022 Volume 14, Issue 11

Abstract: Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant ... ...

Abstract	Hyperoxia is used in order to counteract hypoxia effects in the TME (tumor microenvironment), which are described to boost the malignant tumor phenotype and poor prognosis. The reduction of tumor hypoxic state through the formation of a non-aberrant vasculature or an increase in the toxicity of the therapeutic agent improves the efficacy of therapies such as chemotherapy. Radiotherapy efficacy has also improved, where apoptotic mechanisms seem to be implicated. Moreover, hyperoxia increases the antitumor immunity through diverse pathways, leading to an immunopermissive TME. Although hyperoxia is an approved treatment for preventing and treating hypoxemia, it has harmful side-effects. Prolonged exposure to high oxygen levels may cause acute lung injury, characterized by an exacerbated immune response, and the destruction of the alveolar-capillary barrier. Furthermore, under this situation, the high concentration of ROS may cause toxicity that will lead not only to cell death but also to an increase in chemoattractant and proinflammatory cytokine secretion. This would end in a lung leukocyte recruitment and, therefore, lung damage. Moreover, unregulated inflammation causes different consequences promoting tumor development and metastasis. This process is known as protumor inflammation, where different cell types and molecules are implicated; for instance, IL-1β has been described as a key cytokine. Although current results show benefits over cancer therapies using hyperoxia, further studies need to be conducted, not only to improve tumor regression, but also to prevent its collateral damage.
Language	English
Publishing date	2022-05-31
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14112740
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Article: Endothelial Phosphatase VE-PTP Participates in Vasculogenic Mimicry by Preventing Autophagic Degradation of VE-Cadherin.

Delgado-Bellido, Daniel / Bueno-Galera, Concepción / López-Jiménez, Laura / Garcia-Diaz, Angel / Oliver, F Javier

Frontiers in oncology

2020 Volume 10, Page(s) 18

Abstract: Aberrant extra-vascular expression of VE-cadherin has been observed in metastasis associated with Vasculogenic Mimicry (VM); we have recently shown that in VM prone cells VE-cadherin is mainly in the form of phospho-VE-cadherin in Y658 allowing increased ...

Abstract	Aberrant extra-vascular expression of VE-cadherin has been observed in metastasis associated with Vasculogenic Mimicry (VM); we have recently shown that in VM prone cells VE-cadherin is mainly in the form of phospho-VE-cadherin in Y658 allowing increased plasticity that potentiates VM development in malignant cells. In the current study, we present results to show that human malignant melanoma cells VM+, express the VE-cadherin phosphatase VE-PTP. VE-PTP forms a complex with VE-Cadherin and p120-catenin and the presence of this complex act as a safeguard to prevent VE-Cadherin protein degradation by autophagy. Indeed, VE-PTP silencing results in complete degradation of VE-cadherin with the features of autophagy. In summary, this study shows that VE-PTP is involved in VM formation and disruption of VE-PTP/VE-Cadherin/p120 complex results in enhanced autophagy in aggressive VM
Language	English
Publishing date	2020-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2020.00018
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Article ; Online: Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells.

Calahorra, Jesús / Martínez-Lara, Esther / Granadino-Roldán, José M / Martí, Juan M / Cañuelo, Ana / Blanco, Santos / Oliver, F Javier / Siles, Eva

Scientific reports

2020 Volume 10, Issue 1, Page(s) 6361

Abstract: Olive oil intake has been linked with a lower incidence of breast cancer. Hypoxic microenvironment in solid tumors, such as breast cancer, is known to play a crucial role in cancer progression and in the failure of anticancer treatments. HIF-1 is the ... ...

Abstract	Olive oil intake has been linked with a lower incidence of breast cancer. Hypoxic microenvironment in solid tumors, such as breast cancer, is known to play a crucial role in cancer progression and in the failure of anticancer treatments. HIF-1 is the foremost effector in hypoxic response, and given that hydroxytyrosol (HT) is one of the main bioactive compounds in olive oil, in this study we deepen into its modulatory role on HIF-1. Our results in MCF-7 breast cancer cells demonstrate that HT decreases HIF-1α protein, probably by downregulating oxidative stress and by inhibiting the PI3K/Akt/mTOR pathway. Strikingly, the expression of HIF-1 target genes does not show a parallel decrease. Particularly, adrenomedullin and vascular endothelial growth factor are up-regulated by high concentrations of HT even in HIF-1α silenced cells, pointing to HIF-1-independent mechanisms of regulation. In fact, we show, by in silico modelling and transcriptional analysis, that high doses of HT may act as an agonist of the aryl hydrocarbon receptor favoring the induction of these angiogenic genes. In conclusion, we suggest that the effect of HT in a hypoxic environment is largely affected by its concentration and involves both HIF-1 dependent and independent mechanisms.
MeSH term(s)	Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/genetics ; MCF-7 Cells ; Olive Oil/chemistry ; Olive Oil/pharmacology ; Phenol/chemistry ; Phenol/pharmacology ; Phenylethyl Alcohol/analogs & derivatives ; Phenylethyl Alcohol/metabolism ; Phenylethyl Alcohol/pharmacology ; Phosphatidylinositol 3-Kinases/genetics ; Proto-Oncogene Proteins c-akt/genetics ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/genetics
Chemical Substances	HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; Olive Oil ; 3,4-dihydroxyphenylethanol (10597-60-1) ; Phenol (339NCG44TV) ; MTOR protein, human (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1) ; Phenylethyl Alcohol (ML9LGA7468)
Language	English
Publishing date	2020-04-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-63417-6
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Article ; Online: Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin.

Delgado-Bellido, Daniel / Serrano-Saenz, Santiago / Fernández-Cortés, Mónica / Oliver, F Javier

Molecular cancer

2017 Volume 16, Issue 1, Page(s) 65

Abstract: Vasculogenic mimicry (VM) is a blood supply system independent of endothelial vessels in tumor cells from different origins. It reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature. The presence ... ...

Abstract	Vasculogenic mimicry (VM) is a blood supply system independent of endothelial vessels in tumor cells from different origins. It reflects the plasticity of aggressive tumor cells that express vascular cell markers and line tumor vasculature. The presence of VM is associated with a high tumor grade, short survival, invasion and metastasis. Endothelial cells (ECs) express various members of the cadherin superfamily, in particular vascular endothelial (VE-) cadherin, which is the main adhesion receptor of endothelial adherent junctions. Aberrant extra-vascular expression of VE-cadherin has been observed in certain cancer types associated with VM. In this review we focus on non-endothelial VE-cadherin as a prominent factor involved in the acquisition of tubules-like structures by aggressive tumor cells and we summarize the specific signaling pathways, the association with trans-differentiation and stem-like phenotype and the therapeutic opportunities derived from the in-depth knowledge of the peculiarities of the biology of VE-cadherin and other key components of VM.
MeSH term(s)	Animals ; Biomarkers ; Cadherins/metabolism ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Epithelial-Mesenchymal Transition ; Humans ; Hypoxia/metabolism ; Neoplasms/blood supply ; Neoplasms/metabolism ; Neoplasms/pathology ; Neovascularization, Pathologic/metabolism ; Signal Transduction ; Tumor Microenvironment
Chemical Substances	Biomarkers ; Cadherins
Language	English
Publishing date	2017-03-21
Publishing country	England
Document type	Journal Article ; Review
ISSN	1476-4598
ISSN (online)	1476-4598
DOI	10.1186/s12943-017-0631-x
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Article ; Online: VE-cadherin promotes vasculogenic mimicry by modulating kaiso-dependent gene expression.

Delgado-Bellido, Daniel / Fernández-Cortés, Mónica / Rodríguez, María Isabel / Serrano-Sáenz, Santiago / Carracedo, Arkaitz / Garcia-Diaz, Angel / Oliver, F Javier

Cell death and differentiation

2018 Volume 26, Issue 2, Page(s) 348–361

Abstract: Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with vasculogenic mimicry (VM); however, the ultimate reason why non-endothelial VEC favors the acquisition of this phenotype is not established. In this ... ...

Abstract	Aberrant extra-vascular expression of VE-cadherin (VEC) has been observed in metastasis associated with vasculogenic mimicry (VM); however, the ultimate reason why non-endothelial VEC favors the acquisition of this phenotype is not established. In this study, we show that human malignant melanoma cells have a constitutively high expression of phoshoVEC (pVEC) at Y658; pVEC is a target of focal adhesion kinase (FAK) and forms a complex with p120-catenin and the transcriptional repressor kaiso in the nucleus. FAK inhibition enabled kaiso to suppress the expression of its target genes and enhanced kaiso recruitment to KBS-containing promoters. Finally we have found that ablation of kaiso-repressed genes WNT11 and CCDN1 abolished VM. Thus, identification of pVEC as a component of the kaiso transcriptional complex establishes a molecular paradigm that links FAK-dependent phosphorylation of VEC as a major mechanism by which ectopical VEC expression exerts its function in VM.
MeSH term(s)	Antigens, CD/genetics ; Antigens, CD/metabolism ; Cadherins/genetics ; Cadherins/metabolism ; Catenins/metabolism ; Cell Line, Tumor ; Cyclin D1/genetics ; Focal Adhesion Kinase 1/metabolism ; Gene Expression ; Gene Knockout Techniques ; HEK293 Cells ; Human Umbilical Vein Endothelial Cells ; Humans ; Melanoma/genetics ; Melanoma/pathology ; Neovascularization, Pathologic/genetics ; Phosphorylation ; Skin Neoplasms/genetics ; Skin Neoplasms/pathology ; Transcription Factors/genetics ; Transduction, Genetic ; Wnt Proteins/genetics
Chemical Substances	Antigens, CD ; CCND1 protein, human ; Cadherins ; Catenins ; Transcription Factors ; Wnt Proteins ; Wnt11 protein, human ; ZBTB33 protein, human ; cadherin 5 ; delta catenin ; Cyclin D1 (136601-57-5) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; PTK2 protein, human (EC 2.7.10.2)
Language	English
Publishing date	2018-05-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1225672-9
ISSN	1476-5403 ; 1350-9047
ISSN (online)	1476-5403
ISSN	1350-9047
DOI	10.1038/s41418-018-0125-4
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Zs.A 4230: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 80: Show issues

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Article ; Online: Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation.

Rodriguez-Vargas, José-Manuel / Martin-Hernandez, Kathline / Wang, Wei / Kunath, Nicolas / Suganthan, Rajikala / Amé, Jean-Christophe / Oliver, F Javier / Ye, Jing / Bjørås, Magnar / Dantzer, Françoise

Cell death & disease

2020 Volume 11, Issue 11, Page(s) 954

Abstract: Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain ... ...

Abstract	Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.
MeSH term(s)	Animals ; Astrocytes/cytology ; Astrocytes/metabolism ; Cell Differentiation ; Gene Expression Regulation ; Mechanistic Target of Rapamycin Complex 2/genetics ; Mechanistic Target of Rapamycin Complex 2/metabolism ; Mice ; Mice, Knockout ; NADPH Oxidase 4/genetics ; NADPH Oxidase 4/metabolism ; Neurogenesis ; Poly(ADP-ribose) Polymerases/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction
Chemical Substances	Reactive Oxygen Species ; NADPH Oxidase 4 (EC 1.6.3.-) ; Nox4 protein, mouse (EC 1.6.3.-) ; Poly(ADP-ribose) Polymerases (EC 2.4.2.30) ; Parp2 protein, mouse (EC 2.4.2.30.) ; Mechanistic Target of Rapamycin Complex 2 (EC 2.7.11.1)
Language	English
Publishing date	2020-11-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-020-03167-5
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Article ; Online: Selective modulation by PARP-1 of HIF-1α-recruitment to chromatin during hypoxia is required for tumor adaptation to hypoxic conditions.

Martí, Juan Manuel / Garcia-Diaz, Angel / Delgado-Bellido, Daniel / O'Valle, Francisco / González-Flores, Ariannys / Carlevaris, Onintza / Rodríguez-Vargas, José Manuel / Amé, Jean Christophe / Dantzer, Françoise / King, George L / Dziedzic, Klaudia / Berra, Edurne / de Álava, E / Amaral, A T / Hammond, Ester M / Oliver, F Javier

Redox biology

2021 Volume 41, Page(s) 101885

Abstract: Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ ... ...

Abstract	Background: The adaptation to hypoxia is mainly controlled by the HIF transcription factors. Increased expression/activity of HIF-1α correlates with poor prognosis in cancer patients. PARP-1 inhibitors are used in the clinic to treat BRCAness breast/ovarian cancer and have been shown to regulate the hypoxic response; therefore, their use could be expanded. Methods: In this work by integrating molecular/cell biology approaches, genome-wide ChIP-seq, and patient samples, we elucidate the extent to which PARP-1 exerts control over HIF-1-regulated genes. Results: In human melanoma, PARP-1 and HIF-1α expression are strongly associated. In response to a hypoxic challenge poly(ADP-ribose) (PAR) is synthesized, HIF-1α is post-transcriptionally modified (PTM) and stabilized by PARylation at specific K/R residues located at its C-terminus. Using an unbiased ChIP-seq approach we demonstrate that PARP-1 dictates hypoxia-dependent HIF-recruitment to chromatin in a range of HIF-regulated genes while analysis of HIF-binding motifs (RCGTG) reveals a restriction on the recognition of hypoxia responsive elements in the absence of PARP-1. Consequently, the cells are poorly adapted to hypoxia, showing a reduced fitness during hypoxic induction. Conclusions: These data characterize the fine-tuning regulation by PARP-1/PARylation of HIF activation and suggest that PARP inhibitors might have therapeutic potential against cancer types displaying HIF-1α over-activation.
MeSH term(s)	Breast Neoplasms ; Cell Hypoxia ; Chromatin ; Female ; Humans ; Hypoxia ; Poly(ADP-ribose) Polymerase Inhibitors
Chemical Substances	Chromatin ; Poly(ADP-ribose) Polymerase Inhibitors
Language	English
Publishing date	2021-02-01
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2021.101885
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