Diego Laderach | Universidad de Buenos Aires (original) (raw)

Papers by Diego Laderach

In vitro high-capacity assay to wuantify the clonal heterogeneity in trilineage potential of mese... more In vitro high-capacity assay to wuantify the clonal heterogeneity in trilineage potential of mesenchymal Stem cells reveals a complex hierarchy of lineage commitment. Stem Cells 2010: 28: 788-98. LABORATORIO DE INMUNOPATOLOGÍA Glicómica de la respuesta inmune: el universo de glicanos y lectinas en microambientes inflamatorios y neoplásicos Glycomics of the immune response: the universe of glycans and lectins in inflammatory and neoplasic microenvironments Glicômica da resposta imune: o universo de glicanos e lectinas em microambientes inflamatórios e neoplásicos

Cancers, Sep 9, 2021

This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY

Clinical Cancer Research, Aug 31, 2017

Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to s... more Purpose: Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, we assessed how hemin, a pharmacologic inducer of heme oxygenase-1 (HO-1), has an impact on prostate cancer development in an in vivo conditioning model. Experimental Design: The stroma of C57BL/6 mice was conditioned by subcutaneous administration of hemin prior to TRAMP-C1 tumor challenge. Complementary in vitro and in vivo assays were performed to evaluate hemin effect on both angiogenesis and the immune response. To gain clinical insight, we used prostate cancer patient-derived samples in our studies to assess the expression of HO-1 and other relevant genes. Results: Conditioning resulted in increased tumor latency and decreased initial growth rate. Histologic analysis of tumors grown in conditioned mice revealed impaired vascularization. Hemin-treated human umbilical vein endothelial cells (HUVEC) exhibited decreased tubulogenesis in vitro only in the presence of TRAMP-C1-conditioned media. Subcutaneous hemin conditioning hindered tumor-associated neovascularization in an in vivo Matrigel plug assay. In addition, hemin boosted CD8 þ T-cell proliferation and degranulation in vitro and antigen-specific cytotoxicity in vivo. A significant systemic increase in CD8 þ T-cell frequency was observed in preconditioned tumor-bearing mice. Tumors from hemin-conditioned mice showed reduced expression of galectin-1 (Gal-1), key modulator of tumor angiogenesis and immunity, evidencing persistent remodeling of the microenvironment. We also found a subset of prostate cancer patient-derived xenografts and prostate cancer patient samples with mild HO-1 and low Gal-1 expression levels. Conclusions: These results highlight a novel function of a human-used drug as a means of boosting the antitumor response.

Journal of Autoimmunity, Mar 1, 2003

Objective: To gain insights on initial stages of the autoimmune response in lupus prone mice taki... more Objective: To gain insights on initial stages of the autoimmune response in lupus prone mice taking advantage of new sensitive and quantitative techniques for the detection of autoantibodies specific for RNA-(ribonucleoproteins) and DNA-protein (chromatin) complexes. Methods: DNA and nucleosome antibodies were detected by ELISA, antibodies to SmB, U1A-RNP, Ro52, Ro60 and La by a new radioligand assay, using de novo synthesized radio-labeled antigens. Results: Analysis of anti-chromatin (including anti-nucleosome, anti-dsDNA and anti-histone antibodies) and of anti-snRNP antibodies (including anti-U1A-RNP, anti-SmB, anti-Ro52, anti-Ro60, anti-La antibodies) was performed in sequential sera from B/W, MRL+/+, MRL Yaa and MRL lpr/lpr mice. In a cohort of 105 MRL+/+ mice of different ages, 59, 51, and 57 mice were positive for anti-nucleosome, anti-SmB and anti-U1A-RNP, respectively. None of them was positive for anti-dsDNA. Importantly, antibody positivities were not randomly distributed but were significantly clustered in individual mice. Appearance of DNA-and RNA-protein complex antibodies started at w18-20 weeks of age, preceding that of the anti-dsDNA (or anti-histone) antibodies that only started at 30-32 weeks. Anti-nucleosome, anti-SmB and anti-U1A-RNP antibody responses did not display any cross-reactivity as demonstrated by inhibition and adsorption experiments. Conclusion: These data indicate that anti-nucleosome and anti-snRNP antibodies appear early and concomitantly in lupus prone mice even though they do not share any cross-reactivity. These results fit with the assumption that their production is triggered by tightly physically associated nucleosomes and snRNP autoantigens contained in the same apoptotic bodies.

Journal of Immunology, Aug 15, 2003

A Soluble Factor Secreted by an HIV-1-Resistant Cell Line Blocks Transcription through Inactivati... more A Soluble Factor Secreted by an HIV-1-Resistant Cell Line Blocks Transcription through Inactivating the DNA-Binding Capacity of the NF-κB p65/p50 Dimer

Blood, Nov 15, 2004

Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Kn... more Mature dendritic cells (mDCs) can trigger the effector functions of natural killer (NK) cells. Knockout , small-interfering RNA or neutralizing antibodies targeting interleukin 12 (IL-12) subunits revealed a critical role for IL-12 in NK cell interferon ␥ (IFN-␥) secretion promoted by mDCs. However, NK cell activation by DCs also required direct cell-to-cell contacts. DCmediated NK cell activation involved the formation of stimulatory synapses between DCs and NK cells. The formation of DC/NK cell conjugates depended on cytoskeleton remodeling and lipid raft mobilization in DCs. Moreover, the disruption of the DC cytoskeleton using pharmacologic agents or the loss-of-function mutation of the Wiskott-Aldrich syndrome protein abolished the DC-mediated NK cell activation. Synapse formation promoted the polarized secretion of preassembled stores of IL-12 by DCs toward the NK cell. The synaptic delivery of IL-12 by DCs was required for IFN-␥ secretion by NK cells, as assessed using inhibitors of cytoskeleton rearrangements and transwell experiments. Therefore, the cross-talk between DCs and NK cells is dictated by functional synapses.

Prostate Cancer, 2013

A better understanding of multimolecular interactions involved in tumor dissemination is required... more A better understanding of multimolecular interactions involved in tumor dissemination is required to identify new effective therapies for advanced prostate cancer (PCa). Several groups investigated protein-glycan interactions as critical factors for crosstalk between prostate tumors and their microenvironment. This review both discusses whether the "galectin-signature" might serve as a reliable biomarker for the identification of patients with high risk of metastasis and assesses the galectin-glycan lattices as potential novel targets for anticancer therapies. The ultimate goal of this review is to convey how basic findings related to galectins could be in turn translated into clinical settings for patients with advanced PCa.

Glycobiology, Jun 16, 2014

Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer d... more Prostate cancer is the second most common cause of cancer and the sixth leading cause of cancer death among men worldwide. While localized prostate cancer can be cured, advanced and metastatic prostate cancer remains a significant therapeutic challenge. Malignant transformation is associated with important modifications of the cellular glycosylation profile, and it is postulated that these changes have a considerable relevance for tumor biology. Metastasis is a multiphasic process that encompasses angiogenesis, the spread of tumor cells and their growth at distant sites from the primary tumor location. Recognition of glycoconjugates by galectins, among other lectins, plays a fundamental role in the metastatic spread, tumor immune escape and the neovascularization process. Particularly in prostate cancer, both carbohydrates and galectins have been implicated in many cellular processes such as proliferation, apoptosis, migration and invasion. However, a limited number of studies assessed their potential implications in the induction of metastasis in prostate cancer patients or in animal models. Moreover, the role of galectin-glycan interactions in vivo still remains poorly understood; concerted effort should thus be made in order to shed some light on this question. This review summarizes current evidence on both the expression and role of glycans and galectins in prostate cancer, particularly turning our attention to the angiogenic and metastatic processes.

Cellular Immunology, Nov 1, 2003

Co-stimulation via 4-1BB and its ligand 4-1BB ligand (4-1BB-L) plays an important role in cytotox... more Co-stimulation via 4-1BB and its ligand 4-1BB ligand (4-1BB-L) plays an important role in cytotoxic and pro-inflammatory immune responses. 4-1BB-L is generally described on activated antigen-presenting cells but there is limited information on its expression and function in human dendritic cells (DC). We herein compared purified CD1a+CD14) DC issued from monocytes or from hematopoietic progenitor cells (HPC). These DC expressed 4-1BB-L mRNA transcripts with highest cell surface levels on HPC-derived DC cultured with IL-1. Pro-inflammatory activation, particularly CD40 ligand+IL-1, up-regulated 4-1BB-L on DC. We confirmed reverse signaling via 4-1BB-L as immobilized 4-1BB in conjunction with CD40-L, enhanced IL-12b mRNA and the secretion of IL-12 p70 in various APC, including monocytes. Altogether, DC may differ in T cell co-stimulation properties due to variable and regulated levels of 4-1BB-L. Data illustrate reciprocal stimulations between T cells and APC via up-regulated receptor/ ligands and production of key cytokines that consolidate cellular immune responses.

List of the primers used in qPCR analyses carried out in this study.

Expression of CD146 mRNA levels in control and hemin-treated BAEC (50 μM, 8 h), as determined by ... more Expression of CD146 mRNA levels in control and hemin-treated BAEC (50 μM, 8 h), as determined by RT-qPCR. Bovine GAPDH was used as an internal reference gene. * indicates P<0.05

In vitro tubulogenesis assay. A, in vitro tube formation using control or hemin-treated HUVEC in ... more In vitro tubulogenesis assay. A, in vitro tube formation using control or hemin-treated HUVEC in the absence or presence of T-C1 conditioned media. Complete growth media served as a positive control. Figure depicts one representative out of three independent experiments. B, total tube length was quantified. *** indicates P<0.001

Bioinformatic analysis of human prostate adenocarcinoma microarray datasets. Oncomine was used to... more Bioinformatic analysis of human prostate adenocarcinoma microarray datasets. Oncomine was used to browse gene expression microarrays data. Box plots depict prostate statistics derived from Grasso et al. LGALS1, CD34, FLT1, FLT4, VEGFA, VEGFC, VCAM1, CD28, CD80 and CD86 were assessed. Each box plot shows the expression levels for each gene in 1) normal prostate gland and 2) prostate adenocarcinoma. * indicates P<0.05

Expression microarray studies available in the Oncomine database that met our eligibility criteria.

Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interac... more Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the “galectin signature” of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal-3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor-vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated “galectin-specific signature” that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease. Cancer Res; 73(1); 86–96. ©2012 AACR.

International Journal of Angiology, Sep 1, 1996

Chagas' disease is one of the most common causes of congestive heart failure and sudden death in ... more Chagas' disease is one of the most common causes of congestive heart failure and sudden death in the world. It is manifested by cardiovascular, digestive, and autonomic nervous system disorders with lesion of the conduction system. We have studied the presence of IgG and IgM anti-gangliosides antibodies by enzyme-linked immunosorbent assay (ELISA) and dot blot immune stain in 34 patients with positive serology for Chagas' disease, divided into three groups (G); GI: no cardiac symptoms, normal ECG, and chest X-ray; GII: arrhythmias, left anterior hemiblock (LAHB), complete right bundle branch block (CRBBB), ventricular premature beats (VPB), without signs or symptoms of congestive heart failure; GIII: arrhythmias, LAHB, CRBBB, VPB, congestive heart failure, and cardiomegaly. The percentages of IgG reactive sera against gangliosides (GM1, GDla, GDlb, GTlb) by ELISA were as follows: Group GM1 GDla GDlb GTlb I ll% 0% 11% 0% II 38% 31% 38% 46% lII 42% 50% 33% 67% IgM anti-gangliosides was present only against GTlb in one patient of GI and in one of GII. It is interesting to point out that in Groups II and III patients with signs or symptoms of heart disease, the percentages of positive sera as well as the titers of antibodies against gangliosides were significantly higher than in Group I. The greater cardiac and autonomic damage was associated with the greater reactivity against gangliosides. After the absorption of patient's serum with GM1 ganglioside or with T. cruzi epimastigotes, the percentage of reactivity against GM1 was diminished on a similar proportion suggesting a cross-reactivity between GMI and T. cruzi antigens.

Iubmb Life, 2009

Galectins are a family of evolutionarily conserved animal lectins with pleiotropic functions and ... more Galectins are a family of evolutionarily conserved animal lectins with pleiotropic functions and widespread distribution. Fifteen members have been identified in a wide variety of cells and tissues. Through recognition of cell surface glycoproteins and glycolipids, these endogenous lectins can trigger a cascade of intracellular signaling pathways capable of modulating cell differentiation, proliferation, survival, and migration. These cellular events are critical in a variety of biological processes including embryogenesis, angiogenesis, neurogenesis, and immunity and are substantially altered during tumorigenesis, neurodegeneration, and inflammation. In addition, galectins can modulate intracellular functions and this effect involves direct interactions with distinct signaling pathways. In this review, we discuss current knowledge on the intracellular signaling pathways triggered by this multifunctional family of b-galactosidebinding proteins in selected physiological and pathological settings. Understanding the ''galectin signalosome'' will be essential to delineate rational therapeutic strategies based on the specific control of galectin expression and function.

Journal of Leukocyte Biology, Dec 1, 1998