Santiago Ramón y Cajal - Academia.edu (original) (raw)

Papers by Santiago Ramón y Cajal

Carcinogenesis, Jan 14, 2011

Journal of Clinical Oncology, May 20, 2011

7037 Background: EGFR deregulation has been extensively studied in NSCLC, but less is known about... more 7037 Background: EGFR deregulation has been extensively studied in NSCLC, but less is known about the expression and role of other ErbB receptors. The aim of this study is to determine ErbB2 and ErbB3 expression in NSCLC. METHODS Tumor samples from 126 NSCLC pts who underwent complete resection in our institution from October 2007 to September 2010 were analyzed. Tissue microarrays were used to study ErbB2 and ErbB3 expression by immunohistochemistry; expression was graded by two independent observers and tumors with a 2+/3+ score were classified as "high expression". ErbB2 by FISH was analyzed in pts with high ErbB2 expression. EGFR-mutation (mut) status was determined in selected pts. RESULTS Pts characteristics: median age 67 yrs, 81% male, 6% never smokers, 40% adenocarcinoma (ADC)/ 39% squamous-cell (SCC)/ 21% others, p-stage 33% I/28% II/30% III/9% IV. High ErbB2 expression was found in 5 (4%) pts: all 5 male, 1 never smoker, 3 ADC/2 SCC. None of these pts was ErbB2 FISH+. High ErbB3 membranous and cytoplasmic expression was found in 27% and 21% of samples, respectively, with 10% of samples having high expression at both sites. No correlation was found between ErbB3 expression and age and p-stage. High ErbB3 expression was more frequent in females than in males (membranous 46% vs 22% p= .038; cytoplasmic 33% vs 18% p= .099, respectively), in ADC than in the other histologies (membranous 36% vs 21% p= .07; cytoplasmic 32% vs 13% p =.014, respectively). Five of 23 pts had EGFR-mut (2 del exon 19, 3 L858R exon 21): all 5 female with ADC, 4 never smokers. No EGFR-mut pt had concomitant high ErbB2. Four EGFR-mut pts had high cytoplasmic ErbB3 expression (80%), 3 (60%) had membranous expression. Preliminary results (median follow-up, 17 months) showed no association between ErbB3 expression and disease-free or overall survival, although longer follow-up is needed. CONCLUSIONS High ErbB2 expression is infrequent in NSCLC. ErbB3 can be highly expressed in NSCLC and seems more frequent in females, ADC and EGFR-mut tumors. ErbB3 warrants further study in NSCLC to clarify its role and its potential use as therapeutic target.

Histopathology, May 14, 2019

Frontiers in Cell and Developmental Biology, Nov 18, 2022

Cancers

Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clar... more Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed gene...

International Journal of Molecular Sciences, 2022

Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been wide... more Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenov...

Frontiers in Cell and Developmental Biology, 2021

The invasive tumor front (the tumor–host interface) is vitally important in malignant cell progre... more The invasive tumor front (the tumor–host interface) is vitally important in malignant cell progression and metastasis. Tumor cell interactions with resident and infiltrating host cells and with the surrounding extracellular matrix and secreted factors ultimately determine the fate of the tumor. Herein we focus on the invasive tumor front, making an in-depth characterization of reticular fiber scaffolding, infiltrating immune cells, gene expression, and epigenetic profiles of classified aggressive primary uterine adenocarcinomas (24 patients) and leiomyosarcomas (11 patients). Sections of formalin-fixed samples before and after microdissection were scanned and studied. Reticular fiber architecture and immune cell infiltration were analyzed by automatized algorithms in colocalized regions of interest. Despite morphometric resemblance between reticular fibers and high presence of macrophages, we found some variance in other immune cell populations and distinctive gene expression and ce...

Histology and histopathology, 1998

Gene therapy is understood to be both the restitution of genetic alterations caused by mutation o... more Gene therapy is understood to be both the restitution of genetic alterations caused by mutation or deletion and the control of overexpressed genes. The concept of gene therapy can also encompass molecular strategies to induce cell death in tumor cell by either the so-called "suicided genes" or by certain viral genes that induce a more selective cell death among the transformed cells. The prospect for the clinical application of gene therapy are enormous and, at least theoretically, its utilization can be extended to a number of diseases known to have a genetic basis, and to neoplastic processes. This review summarizes some of the projects that are currently underway involving neoplastic diseases, liver diseases, hematopoietic cells and respiratory tract cells. The results of most of the ongoing protocols are not yet conclusive, and presumibly, their clinical application is still some years away. One of the major limitations is the method of introducing the genetic sequence...

Clinical Cancer Research, 2020

Introduction: Previous studies have shown that levels of circulating tumor DNA (ctDNA) during the... more Introduction: Previous studies have shown that levels of circulating tumor DNA (ctDNA) during therapy and post-surgery can stratify patients who exhibit effective responses versus those showing minimal residual disease. In this study, we performed longitudinal tracking of plasma TP53 and PIK3CA mutations prespecified from NGS analysis of tumor tissue specimens of HER2-positive and triple-negative (TN) breast cancer (BC) patients in order to demonstrate that ctDNA clearance during neoadjuvant treatment (NAT) correlates with effective response to treatment. Initially, we examined the degree to which clearance of TP53 and PIK3CA mutations in ctDNA during NAT correlated with pathologic complete response (pCR) in the resected specimen. Our findings suggest that effective ctDNA clearance may predict pCR. Moreover, these findings prompt further investigative trials that explore more fully the value of ctDNA monitoring to identify those patients who may avoid surgery following NAT. Patients...

Journal of Molecular Medicine, 2020

In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and... more In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Functionally, heterogeneity provides tumors with significant adaptability. This ranges from mutual beneficial cooperation between cells, which nurture features such as growth and metastasis, to the narrow escape and survival of clonal cell populations that have adapted to thrive under specific conditions such as hypoxia or chemotherapy. These dynamic intercellular interplays are guided by a Darwinian selection landscape between clonal tumor cell populations and the tumor microenvironment. Understanding the involved drivers and functional consequences of such tumor heterogeneity is challenging but also promises to provide novel insight needed to confront the problem of thera...

Clinical and Translational Oncology, 2019

Direct intercellular communication, mediated by gap junctions formed by the connexin transmembran... more Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tum...

Oncotarget, Jan 17, 2018

Brain metastases constitute a challenge in the management of patients with HER2-positive breast c... more Brain metastases constitute a challenge in the management of patients with HER2-positive breast cancer treated with anti-HER2 systemic therapies. Here we sought to define the repertoire of mutations private to or enriched for in HER2-positive brain metastases. Massively parallel sequencing targeting all exons of 254 genes frequently mutated in breast cancers and/or related to DNA repair was used to characterize the spatial and temporal heterogeneity of HER2-positive breast cancers and their brain metastases in six patients. Data were analyzed with state-of-the-art bioinformatics algorithms and selected mutations were validated with orthogonal methods. Spatial and temporal inter-lesion genetic heterogeneity was observed in the HER2-positive brain metastases from an index patient subjected to a rapid autopsy. Genetic alterations restricted to the brain metastases included mutations in cancer genes and , homozygous deletion in and amplification in . Shifts in clonal composition and the...

Cell death & disease, Oct 26, 2017

Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA... more Lung cancer is one of the most aggressive tumours with very low life expectancy. Altered microRNA expression is found in human tumours because it is involved in tumour growth, progression and metastasis. In this study, we analysed microRNA expression in 47 lung cancer biopsies. Among the most downregulated microRNAs we focussed on the miR-99a characterisation. In vitro experiments showed that miR-99a expression decreases the proliferation of H1650, H1975 and H1299 lung cancer cells causing cell cycle arrest and apoptosis. We identified two novel proteins, E2F2 (E2F transcription factor 2) and EMR2 (EGF-like module-containing, mucin-like, hormone receptor-like 2), downregulated by miR-99a by its direct binding to their 3'-UTR. Moreover, miR-99a expression prevented cancer cell epithelial-to-mesenchymal transition (EMT) and repressed the tumourigenic potential of the cancer stem cell (CSC) population in both these cell lines and mice tumours originated from H1975 cells. The expres...

Postgraduate Medical Journal, 1999

Summary Typical Cogan's syndrome is a rare disease of young adults consisting of flares of in... more Summary Typical Cogan's syndrome is a rare disease of young adults consisting of flares of interstitial keratitis and sudden onset of Ménière-like attacks (nausea, vomiting, tinnitus, vertigo and hearing loss). Life-threatening aortic insufficiency develops in 10% of reported cases. Atypical Cogan's syndrome (audiovestibular dysfunction with other types of inflammatory eye disease) is associated with vasculitis in 20% of cases and has a less favourable prognosis than typical Cogan's syndrome.

Revista Española de Patología, 2015