Aránzazu Sánchez

Universidad Complutense de Madrid

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Isabel Fabregat

Institut d'Investigació Biomédica de Bellvitge

Blanca Herrera

Hospital Clínico San Carlos

Cesáreo Roncero

Universidad Complutense de Madrid

Margarita Fernández

Pennsylvania State University

Manuel Benito

Universidad Complutense de Madrid

Annalisa Addante

Charité - Universitätsmedizin Berlin

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Alberto Álvarez

Universidad de Extremadura

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Ángela M. Valverde

Universidad Autónoma de Madrid

Valentina M. Factor

National Cancer Institute

Esther Bertrán

Institut d'Investigació Biomédica de Bellvitge

Cooperative Institutions

Universidad Complutense de Madrid

Heidelberg University

Instituto de Salud Carlos III

University Hospital Heidelberg

Universidad Autónoma de Madrid

Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

Consejo Superior de Investigaciones Científicas

University Medical Centre Mannheim

Centro de Investigación Biomédica en Red

Hospital Clínico San Carlos

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Correction to Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer Agents

Journal of Medicinal Chemistry (2016)

Luciano De Petrocellis F.J. Arroyo Pierangelo Orlando Aniello Schiano Moriello Rosa Maria Vitale

ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionNEXTORIGINAL ARTICLEThis notice is a correctionCorrection to Tetrahydroisoquinoline-Derived Urea and 2,5-Diketopiperazine Derivatives as Selective Antagonists of the Transient Receptor Potential Melastatin 8 (TRPM8) Channel Receptor and Antiprostate Cancer AgentsLuciano De Petrocellis*, Francisco J. Arroyo, Pierangelo Orlando, Aniello Schiano Moriello, Rosa Maria Vitale, Pietro Amodeo, Aránzazu Sánchez, Cesáreo Roncero, Giulia Bianchini, M. Antonia Martín, Pilar López-Alvarado, and J. Carlos Menéndez*Cite this: J. Med. Chem. 2016, 59, 16, 7697Publication Date (Web):August 3, 2016Publication History Published online3 August 2016Published inissue 25 August 2016https://pubs.acs.org/doi/10.1021/acs.jmedchem.6b01091https://doi.org/10.1021/acs.jmedchem.6b01091correctionACS PublicationsCopyright © 2016 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views824Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (115 KB) Get e-Alertsclose Get e-Alerts

Tetrahydroisoquinoline

10.1021/acs.jmedchem.6b01091

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Citations (0)

272 In vitro differentiation of adult liver stem cells into the hepatocytic lineage

Hepatology (2003)

Insa S. Schroeder Valentina M. Factor Aránzazu Sánchez Ji‐Hyun Lee T HOANG

Lineage (genetic)

10.1016/s0270-9139(03)80315-4

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Citations (1)

Case Report: An EGFR-Targeted 4-1BB-agonistic Trimerbody Does Not Induce Hepatotoxicity in Transgenic Mice With Liver Expression of Human EGFR

Frontiers in Immunology (2021)

Marta Compte Seandean L. Harwood Jorge L. Martínez‐Torrecuadrada Gema Pérez-Chacón Patricia González‐García

Agonistic monoclonal antibodies (mAbs) targeting the co-stimulatory receptor 4-1BB are among the most effective immunotherapeutic agents across pre-clinical cancer models. However, clinical development of full-length 4-1BB agonistic mAbs, has been hampered by dose-limiting liver toxicity. We have previously developed an EGFR-targeted 4-1BB-agonistic trimerbody (1D8N/CEGa1) that induces potent anti-tumor immunity without systemic toxicity, in immunocompetent mice bearing murine colorectal carcinoma cells expressing human EGFR. Here, we study the impact of human EGFR expression on mouse liver in the toxicity profile of 1D8N/CEGa1. Systemic administration of IgG-based anti-4-1BB agonist resulted in nonspecific immune stimulation and hepatotoxicity in a liver-specific human EGFR-transgenic immunocompetent mouse, whereas in 1D8N/CEGa1-treated mice no such immune-related adverse effects were observed. Collectively, these data support the role of FcγR interactions in the major off-tumor toxicities associated with IgG-based 4-1BB agonists and further validate the safety profile of EGFR-targeted Fc-less 4-1BB-agonistic trimerbodies in systemic cancer immunotherapy protocols.

Agonistic behaviour

10.3389/fimmu.2020.614363

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Citations (8)

Transforming growth factor β modulates growth and differentiation of fetal hepatocytes in primary culture

Journal of Cellular Physiology (1995)

Aránzazu Sánchez Alberto Álvarez Manuel Benito Isabel Fabregat

Fetal hepatocytes in primary culture are cells capable to carry out both proliferation and differentiation processes simultaneously. Previous studies have shown that these cells respond to mitogens, such as hepatocyte growth factor (HGF) or epidermal growth factor (EGF), inducing the expression of early genes, such as fos and myc. The transforming growth factor-β (TGF-β) family is one of the most influential groups of growth and differentiation factors. In this report, we show that TGF-β-1 inhibits fetal hepatocyte proliferation, arresting these cells at G1 phase of the cell cycle. In addition, TGF-β down-regulates the mitogen-induced myc early expression. However, TGF-β has no effect on the expression of other protooncogenes, such as fos and H-ras. In addition to its inhibitory role on fetal hepatocyte growth, TGF-β increases the mRNA levels of fibronectin, an extracellular matrix protein, and maintains the expression of some liver specific genes, such as albumin and alfafetoprotein, above control values. The analysis of the expression of some hepatocyte transcriptional factors has shown that TGF-β increases HNF1α and HNF1β mRNA levels. We conclude that TGF-β may modulate liver growth and differentiation throughout fetal development. © 1995 Wiley-Liss, Inc.

10.1002/jcp.1041650221

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Mouse Hepatic Oval Cells Require Met-Dependent PI3K to Impair TGF-β-Induced Oxidative Stress and Apoptosis

PLoS ONE (2013)

Adoración Martínez‐Palacián Gaelle del Castillo Amileth Suárez Causado María García‐Álvaro Diego de la Morena-Frutos

We have previously shown that oval cells harboring a genetically inactivated Met tyrosine kinase (Met−/− oval cells) are more sensitive to TGF-β-induced apoptosis than cells expressing a functional Met (Metflx/flx), demonstrating that the HGF/Met axis plays a pivotal role in oval cell survival. Here, we have examined the mechanism behind this effect and have found that TGF-β induced a mitochondria-dependent apoptotic cell death in Metflx/flx and Met−/− oval cells, associated with a marked increase in levels of the BH3-only proteins Bim and Bmf. Bmf plays a key role during TGF-β-mediated apoptosis since knocking down of BMF significantly diminished the apoptotic response in Met−/− oval cells. TGF-β also induced oxidative stress accompanied by NADPH oxidase 4 (Nox4) mRNA up-regulation and decreased protein levels of antioxidant enzymes. Antioxidants inhibit both TGF-β-induced caspase 3 activity and Bmf up-regulation, revealing an oxidative stress-dependent Bmf regulation by TGF-β. Notably, oxidative stress-related events were strongly amplified in Met−/− oval cells, emphasizing the critical role of Met in promoting survival. Pharmacological inhibition of PI3K did impair HGF-driven protection from TGF-β-induced apoptosis and increased sensitivity of Metflx/flx oval cells to TGF-ß by enhancing oxidative stress, reaching apoptotic indices similar to those obtained in Met−/− oval cells. Interestingly, both PI3K inhibition and/or knockdown itself resulted in caspase-3 activation and loss of viability in Metflx/flx oval cells, whereas no effect was observed in Met−/− oval cells. Altogether, results presented here provide solid evidences that both paracrine and autocrine HGF/Met signaling requires PI3K to promote mouse hepatic oval cell survival against TGF-β-induced oxidative stress and apoptosis.

10.1371/journal.pone.0053108

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Clathrin switches transforming growth factor-β role to pro-tumorigenic in liver cancer

Journal of Hepatology (2019)

Daniel Caballero‐Díaz Esther Bertrán Irene Peñuelas‐Haro Joaquim Moreno‐Càceres Andrea Malfettone

Upon ligand binding, tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR), are recruited into clathrin-coated pits for internalization by endocytosis, which is relevant for signalling and/or receptor degradation. In liver cells, transforming growth factor-β (TGF-β) induces both pro- and anti-apoptotic signals; the latter are mediated by the EGFR pathway. Since EGFR mainly traffics via clathrin-coated vesicles, we aimed to analyse the potential role of clathrin in TGF-β-induced signalling in liver cells and its relevance in liver cancer.Real-Time PCR and immunohistochemistry were used to analyse clathrin heavy-chain expression in human (CLTC) and mice (Cltc) liver tumours. Transient knockdown (siRNA) or overexpression of CLTC were used to analyse its role on TGF-β and EGFR signalling in vitro. Bioinformatic analysis was used to determine the effect of CLTC and TGFB1 expression on prognosis and overall survival in patients with hepatocellular carcinoma (HCC).Clathrin expression increased during liver tumorigenesis in humans and mice. CLTC knockdown cells responded to TGF-β phosphorylating SMADs (canonical signalling) but showed impairment in the anti-apoptotic signals (EGFR transactivation). Experiments of loss or gain of function in HCC cells reveal an essential role for clathrin in inhibiting TGF-β-induced apoptosis and upregulation of its pro-apoptotic target NOX4. Autocrine TGF-β signalling in invasive HCC cells upregulates CLTC expression, switching its role to pro-tumorigenic. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival.This work describes a novel role for clathrin in liver tumorigenesis, favouring non-canonical pro-tumorigenic TGF-β pathways. CLTC expression in human HCC samples could help select patients that would benefit from TGF-β-targeted therapy.Clathrin heavy-chain expression increases during liver tumorigenesis in humans (CLTC) and mice (Cltc), altering the cellular response to TGF-β in favour of anti-apoptotic/pro-tumorigenic signals. A positive correlation between TGFB1 and CLTC was found in HCC cells and patients. Patients expressing high levels of TGFB1 and CLTC had a worse prognosis and lower overall survival. CLTC expression in HCC human samples could help select patients that would benefit from therapies targeting TGF-β.

10.1016/j.jhep.2019.09.012

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Citations (35)

Isolation and characterization of a putative liver progenitor population after treatment of fetal rat hepatocytes with TGF‐Beta

Journal of Cellular Physiology (2008)

Gaelle del Castillo Alberto Álvarez Irene Carmona‐Cuenca Margarita Fernández Aránzazu Sánchez

Abstract The “in vitro” establishment of a physiological model of bipotential liver progenitors would be useful for analyzing the molecular mechanisms involved in regulating growth and differentiation, as well as studying their potential role/s in liver physiology and pathology. The transforming growth factor‐beta (TGF‐β) induces de‐differentiation of fetal rat hepatocytes (FH), concomitant with changes in morphology. The aim of this work was to isolate and characterize this population of TGF‐β‐treated fetal hepatocytes (TβT‐FH) and test whether they can behave as liver progenitors. The TβT‐FH isolated cell lines show high expression of Thy‐1 and low expression of c‐Kit. They express liver‐specific proteins, such as albumin and alpha‐fetoprotein, and mesenchymal markers, such as vimentin. TβT‐FH maintain expression of the hnf3β gene, but lose expression of hnf1β , hnf4 , and hnf6 . They express c‐met and show an increase in proliferation in response to HGF. Interestingly, the transdifferentiation process is coincident with changes in the expression of genes related to the oxidative metabolism. TβT‐FH cultured in the presence of EGF + DMSO change morphology, towards epithelial cells, gaining expression of CK19 and c‐Kit, markers found in hepatoblasts and bile duct cells. Furthermore, TβT‐FH form duct‐like structures when cultured on Matrigel. TβT‐FH show also potential to revert to an hepatocyte phenotype when submitted to a long‐term “in vitro” differentiation protocol towards hepatocytic lineage. In summary, our results support the hypothesis that hepatocytes can function as facultative liver stem cells and demonstrate that TGF‐β might play an essential role in the transdifferentiation process. J. Cell. Physiol. 215: 846–855, 2008. © 2008 Wiley‐Liss, Inc.

Transdifferentiation

10.1002/jcp.21370

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Citations (21)

Intestinal BMP-9 locally upregulates FGF19 and is down-regulated in obese patients with diabetes

Molecular and Cellular Endocrinology (2023)

Stephan Drexler Chen Cai Anna-Lena Hartmann Denise Moch H Gaitantzi

Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context. We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO- and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples. In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplementation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis.

FGF19

10.1016/j.mce.2023.111934

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Citations (5)

TGF‐β signalling and liver disease

FEBS Journal (2016)

Isabel Fabregat Joaquim Moreno‐Càceres Aránzazu Sánchez Steven Dooley Bedair Dewidar

The transforming growth factor-beta (TGF-β) family signalling pathways play essential roles in the regulation of different cellular processes, including proliferation, differentiation, migration or cell death, which are essential for the homeostasis of tissues and organs. Because of the diverse and pleiotropic TGF-β functions, deregulation of its pathways contributes to human disease. In the case of the liver, TGF-β signalling participates in all stages of disease progression, from initial liver injury through inflammation and fibrosis, to cirrhosis and cancer. TGF-β has cytostatic and apoptotic effects in hepatocytes, promoting liver differentiation during embryogenesis and physiological liver regeneration. However, high levels of TGF-β, as a consequence of chronic liver damage, result in activation of stellate cells to myofibroblasts and massive hepatocyte cell death, which contributes to the promotion of liver fibrosis and later cirrhosis. During liver tumorigenesis, TGF-β may behave as a suppressor factor at early stages; however, there is strong evidence that overactivation of TGF-β signalling might contribute to later tumour progression, once cells escape from its cytostatic effects. For these reasons, targeting the TGF-β signalling pathway is being explored to counteract liver disease progression. In this review, we aim to shed light on the state-of-the-art in the signalling pathways induced by TGF-β that are involved in different stages of liver physiology and pathology.

Liver Regeneration

Liver disease

Liver Cancer

Hepatic stellate cell

10.1111/febs.13665

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Citations (522)

Oncological transformation in vitro of hepatic progenitor cell lines isolated from adult mice

Scientific Reports (2022)

Rocío Olivera-Salazar Mariano García‐Arranz Aránzazu Sánchez Susana Olmedillas‐López Luz Vega-Clemente

Abstract Colorectal cancer cells can transfer the oncogene KRAS to distant cells, predisposing them to malignant transformation (Genometastasis Theory). This process could contribute to liver metastasis; besides, hepatic progenitor cells (HPCs) have been found to be involved in liver malignant neoplasms. The objective of this study is to determine if mouse HPCs—Oval cells (OCs)—are susceptible to incorporate Kras GAT (G12D) mutation from mouse colorectal cancer cell line CT26.WT and if OCs with the incorporated mutation behave like malignant cells. To achieve this, three lines of OCs in different conditions were exposed to CT26.WT cells through transwell co-culture for a week. The presence of Kras G12D and capacity to form tumors were analyzed in treated samples by droplet digital PCR and colony-forming assays, respectively. The results showed that the Kras G12D mutation was detected in hepatic culture conditions of undifferentiated OCs and these cells were capable of forming tumors in vitro. Therefore, OCs are susceptible to malignant transformation by horizontal transfer of DNA with Kras G12D mutation in an undifferentiated condition associated with the liver microenvironment. This study contributes to a new step in the understanding of the colorectal metastatic process.

Malignant Transformation

10.1038/s41598-022-06427-w

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Citations (8)