L M Antón Aparicio

University of A Coruña, La Corogne, Galicia, Spain

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Publications (74)198.72 Total impact

  • [Show abstract] [Hide abstract] ABSTRACT: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6 %) patients were male, 64 (48.1 %) had pancreatic NET, 23 (17.3 %) had ECOG PS ≥2, 41 (30.8 %) had functioning tumours, 63 (47.7 %) underwent surgery of the primary tumour, 45 (33.8 %) had received prior chemotherapy, and 115 (86.5 %) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5 % (6 months), 68.6 % (12 months) and 57.0 % (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3 % (6 months), 73.0 % (12 months), and 67.4 % (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95 % CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.
    No preview · Article · Jul 2015 · BMC Cancer
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    [Show abstract] [Hide abstract] ABSTRACT: In the last few years, the role of epithelial cell plasticity in cancer biology research has gained increasing attention. This concept refers to the ability of the epithelial cells to dynamically switch between different phenotypic cellular states. This program is particularly relevant during the epithelial-to-mesenchymal transition (EMT) in cancer progression. During colonization, epithelial cells first activate the EMT program to disseminate from a primary tumour to reach a distant tissue site. During this process, cells are transported into the circulation and are able to escape the immune system of the host. Then, a reverse process called mesenchymal-to-epithelial transition (MET) occurs on cells that settle in the distant organs. Although epithelial cell plasticity has an important impact on tumour biology, the clinical relevance of this concept remains to be recapitulated. In this review, we will update the current state of epithelial cell plasticity in cancer progression and its clinical implications for the design of therapeutic strategies, the acquisition of multidrug resistance, and future perspectives for the management of cancer patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Full-text · Article · Jun 2015 · Cancer letters
  • Luis León · Enrique Grande · Luis Aparicio
    No preview · Chapter · Apr 2015
  • [Show abstract] [Hide abstract] ABSTRACT: Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients. In this article, most relevant data published in the literature have been reviewed, with special attention to the therapeutic alternatives currently available for postdocexatel mCRPC patients, emphasising the mechanisms of action of the different drugs, efficacy and quality of life-related aspects. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jan 2015 · Cancer Treatment Reviews
  • [Show abstract] [Hide abstract] ABSTRACT: Radionuclides have been widely used for cancer treatment. Recently, new research about radium-223 dichloride has been conducted in prostate cancer, which reveals that it is the first radiopharmaceutical to demonstrate an improvement in overall survival and time to first symptomatic skeletal event in patients with castration resistant prostate cancer with symptomatic bone metastases. This fact has created a new paradigm in the treatment of prostate cancer landscape, where only chemotherapy and hormone therapy had a role, while β-emitters had been confined exclusively to the role of pain relief with no impact on survival. The aim of this review is to outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 dichloride, reviewing patients' profile that make them suitable to therapy and chances for further studies.
    No preview · Article · Jan 2015 · Expert Review of Anti-infective Therapy
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    [Show abstract] [Hide abstract] ABSTRACT: Background Vinflunine (VFL) is a microtubule-targeting drug that suppresses microtubule dynamics, showing anti-metastatic properties both in vitro and in living cancer cells. An increasing body of evidence underlines the influence of the microtubules dynamics on the cadherin-dependent cell-cell adhesions. E-cadherin is a marker of epithelial-to-mesenchymal transition (EMT) and a tumour suppressor; its reduced levels in carcinoma are associated with poor prognosis. In this report, we investigate the role of VFL on cell-cell adhesions in bladder epithelial tumour cells. Methods Human bladder epithelial tumour cell lines HT1376, 5637, SW780, T24 and UMUC3 were used to analyse cadherin-dependent cell-cell adhesions under VFL treatment. VFL effect on growth inhibition was measured by using a MTT colorimetric cell viability assay. Western blot, immunofluorescence and transmission electron microscopy analyses were performed to assess the roles of VFL effect on cell-cell adhesions, epithelial-to-mesenchymal markers and apoptosis. The role of the proteasome in controlling cell-cell adhesion was studied using the proteasome inhibitor MG132. Results We show that VFL induces cell death in bladder cancer cells and activates epithelial differentiation of the remaining living cells, leading to an increase of E-cadherin-dependent cell-cell adhesion and a reduction of mesenchymal markers, such as N-cadherin or vimentin. Moreover, while E-cadherin is increased, the levels of Hakai, an E3 ubiquitin-ligase for E-cadherin, were significantly reduced in presence of VFL. In 5637, this reduction on Hakai expression was blocked by MG132 proteasome inhibitor, indicating that the proteasome pathway could be one of the molecular mechanisms involved in its degradation. Conclusions Our findings underscore a critical function for VFL in cell-cell adhesions of epithelial bladder tumour cells, suggesting a novel molecular mechanism by which VFL may impact upon EMT and metastasis.
    Full-text · Article · Jul 2014 · BMC Cancer
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Based on the TROPIC study results, cabazitaxel was approved for the management of metastatic castration-resistant prostate cancer (mCRPC) progressing on or after docetaxel. Methods: This multi-centre program provided early access to cabazitaxel to patients with mCRPC before its commercialization. Safety data from 153 Spanish patients receiving cabazitaxel 25 mg/m(2) i.v. Q3W, plus oral prednisone/prednisolone 10 mg daily, are reported. Results: Median age of patients was 70 years (26.8% ≥ 75 years), 94.1 and 26.8% had bone and visceral metastasis, respectively. Most had an Eastern Cooperative Oncology Group ≤ 1 (88.9%) and had received a median of 8.0 cycles of last docetaxel treatment. The median of cabazitaxel cycles and cumulative dose were 6.0 (Interquartile range [IQR]: 4.0; 8.0) and 148.9 (IQR: 98.2; 201.4) mg/m(2), respectively. Adverse events (AEs) possibly related to cabazitaxel occurred in 143 (93.5%) patients. The most frequent grade ≥ 3 AEs were neutropenia (n = 25, 16.3%) and asthenia (n = 17, 11.1%). Febrile neutropenia and grade ≥ 3 diarrhea occurred in 5.2% of the patients each. There were five (3.3%) possibly treatment-related deaths, mainly infection-related. G-CSFs were used in 114 (74.5%) patients, generally as prophylaxis (n = 107; 69.9%). Grade ≥ 3 peripheral neuropathy and nail disorders were uncommon. Conclusions: Cabazitaxel administration, in a real-world setting, is tolerated by Spanish patients with mCRPC, and the AEs are manageable.
    No preview · Article · Jul 2014 · Expert Opinion on Drug Safety
  • Guadalupe Aparicio Gallego · Enrique Grande · Luis Antón Aparicio
    [Show abstract] [Hide abstract] ABSTRACT: In 1978, Schofield hypothesized the existence of cells in the proximity of stem cells, termed the stem cell niche, that have the ability to extrinsically exert influence on stem cell behavior. Indeed, a large body of evidence from a number of stem cell systems validated this hypothesis by affirming the critical importance of stem cell niche interactions and localized extracellular signals in regulating stem cell self-renewal and differentiation. This concept is precisely illustrated in the bone marrow transplantation setting in which the success of the transplant is contingent on the ability of hematopoietic stem cells (HSCs) to home and seed appropriate secondary supportive niches of intravenous infection. Experiments using parabiosis of genetically marked strains of mice demonstrated that HSCs constitutively migrate through blood and are able to re-engraft unconditioned bone marrow to niche function HSCs have emerged as the model system to study tissue-specific niche stem cells and their potential to regenerating secondary niche. This chapter reviews observations, olds and recents, suggesting that this plasticity may perhaps outstrech the marrow boundaries, so that HSCs (mesodermal in origin) can give rise to cells that normally derive from germ layers other than the mesoderm. This review discusses the inextricable relationship between adult stem cells and bone marrow-derived hematopoietic cells, and their roles in replenish adult stem cell niches.
    No preview · Article · Jan 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Although investigation in Cancer Stem Cells (CSC) has been more intensive in leukemia or breast cancer, genitourinary tumors, specially prostate cancer, are an important focus of attention in this field. Prostate cancer is the second leading cause of cancer death in men after lung cancer, and Cancer Stem Cells have been proposed as one of the mechanisms of resistance to hormonal treatment and chemotherapy. Epithelial to Mesenchimal Transition is believed to be associated with drug-resistance in prostate cancer, and Wnt, Notch and Hedgehog are implicated in this phenomenon. In the case of bladder cancer it is believed that the CSCs present in urothelial tumors may originate in the basal layers of these organs. Concerning the stem cell origin of renal CSCs, the data are still discordant. The lack of CD133+ marker in renal CSCs may support the idea of an origin from a yet unidentified mesenchymal population. In this chapter authors review the most important data on the role of cancer stem cells in the initiation and development of prostate, bladder and kidney cancer.
    No preview · Article · Jan 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Docetaxel is the standard first-line chemotherapy for men with metastatic castration-resistant prostate cancer. Until recently, there was no standard therapy after failure of docetaxel treatment. Cabazitaxel has been shown to improve overall survival in this setting. As a result, the treatment paradigm for mCRPC is changing rapidly. The improved survival shown with cabazitaxel provides an important new opportunity to treat men with mCRPC after docetaxel treatment. Despite the toxicity recorded in the pivotal study, subsequent trials have shown that cabazitaxel is a safe drug. Patient selection and the optimal interval between prior docetaxel treatment and cabazitaxel remain the critical issues. According to a subanalysis of the various studies discussed in this review, there is a patient profile that will probably benefit from use of cabazitaxel after docetaxel failure. Cabazitaxel represents a new treatment option for patients with prostate cancer.
    No preview · Article · Nov 2013 · Anti-cancer drugs
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    [Show abstract] [Hide abstract] ABSTRACT: Epithelial-to-mesenchymal transition (EMT), one of the crucial steps for carcinoma cells to acquire invasive capacity, results from the disruption of cell-cell contacts and the acquisition of a motile mesenchymal phenotype. Although the transcriptional events controlling EMT have been extensively studied, in recent years, several posttranscriptional mechanisms have emerged as critical in the regulation of EMT during tumor progression. In this review, we highlight the regulation of posttranscriptional events in EMT by RNA-binding proteins (RBPs). RBPs are responsible for controlling pre-mRNA splicing, capping, and polyadenylation, as well as mRNA export, turnover, localization, and translation. We discuss the most relevant aspects of RBPs controlling the metabolism of EMT-related mRNAs, and describe the implication of novel posttranscriptional mechanisms regulating EMT in response to different signaling pathways. Novel insight into posttranscriptional regulation of EMT by RBPs is uncovering new therapeutic targets in cancer invasion and metastasis.
    Full-text · Article · May 2013 · Cellular and Molecular Life Sciences CMLS
  • No preview · Article · Apr 2013 · The Journal of Urology
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: Analysis of a microRNA that is not predicted to interact with Hakai mRNA. A, effect of the indicated transfected pre-miR-21, anti-miR-21 or scrambled Ctrl miRNA on Hakai levels tested in HeLa whole-cell lysates. Analysis was carried out by Western blotting using Hakai antibody and α-tubulin antibody as loading control. The western blotting data are representative of three independent experiments. B, Quantification by densitometry of the Western blotting signals. Values are the means ± SEM from three independent experiments. Student’s T-test analyses indicate no significantly difference relative to scrambled (Ctrl.) miRNA (p>0.25, n = 3). (EPS)
    Full-text · Dataset · Dec 2012
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    Dataset: Figure S3
    [Show abstract] [Hide abstract] ABSTRACT: Influence of the indicated miRNAs on pEGFP-Hakai constructs. Forty-eight h after cotransfection of HeLa cells with pEGFP-Hakai construct together with Pre-miR-203, Anti-miR-203 or scrambled Ctrl miRNA, the levels of GFP and α-tubulin (loading control) were measured by Western blot analysis by using anti-GFP and anti-α-tubulin antibodies. Western blotting data are representative of two independent experiments. (EPS)
    Full-text · Dataset · Dec 2012
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: E-cadherin expression in the indicated epithelial cell lines. Western blot analysis was carried to detect E-cadherin; α-tubulin signals were assessed as loading control. (EPS)
    Full-text · Dataset · Dec 2012
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    Dataset: Figure S4
    [Show abstract] [Hide abstract] ABSTRACT: Quantification of Hakai immunohistochemical staining. Values are the means ± S.E.M of the staining intensity signal scoring per area. Calibration and quantification of the images were performed with AnalySISD 5.0 software. Mann-Whitney U test analyses show statistical differences in tumour samples respect to paired healthy samples (***p<0.001, n = 19). (EPS)
    Full-text · Dataset · Dec 2012
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    [Show abstract] [Hide abstract] ABSTRACT: Gene expression is potently regulated through the action of microRNAs (miRNAs). Here, we present evidence of a miRNA regulating Hakai protein. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin, a major component of adherens junctions in epithelial cells and a potent tumour suppressor. Recent data have provided evidence that Hakai affects cell proliferation in an E-cadherin-independent manner, thus revealing a role for Hakai in the early stages of tumour progression. Furthermore, Hakai is highly up-regulated in human colon adenocarcinomas compared to normal tissues. However, the molecular mechanisms that regulate Hakai abundance are unknown. We identified two putative sites of miR-203 interaction on the Hakai mRNA, in its 3'-untranslated region (UTR). In several human carcinoma cell lines tested, overexpression of a miR-203 precursor (Pre-miR-203) reduced Hakai abundance, while inhibiting miR-203 by using an antisense RNA (Anti-miR-203) elevated Hakai levels. The repressive influence of miR-203 on the Hakai 3'-UTR was confirmed using heterologous reporter constructs. In keeping with Hakai's proliferative influence, Anti-miR-203 significantly increased cell number and BrdU incorporation, while Pre-miR-203 reduced these parameters. Importantly, the growth-promoting effects of anti-miR-203 required the presence of Hakai, because downregulation of Hakai by siRNA suppressed its proliferative action. Finally, in situ hybridization showed that miR-203 expression is attenuated in colon tumour tissues compared to normal colon tissues, suggesting that miR-203 could be a potential new prognostic marker and therapeutic target to explore in colon cancer. In conclusion, our findings reveal, for the first time, a post-transcriptional regulator of Hakai expression. Furthermore, by lowering Hakai abundance, miR-203 also reduces Hakai-regulated-cell division.
    Full-text · Article · Dec 2012 · PLoS ONE
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    [Show abstract] [Hide abstract] ABSTRACT: Historically, cell-signaling pathways have been studied as the compilation of isolated elements into a unique cascade that transmits extracellular stimuli to the tumor cell nucleus. Today, growing evidence supports the fact that intracellular drivers of tumor progression do not flow in a single linear pathway, but disseminate into multiple intracellular pathways. An improved understanding of the complexity of cancer depends on the elucidation of the underlying regulatory networks at the cellular and intercellular levels and in their temporal dimension. The high complexity of the intracellular cascades causes the complete inhibition of the growth of one tumor cell to be very unlikely, except in cases in which the so-called “oncogene addiction” is known to be a clear trigger for tumor catastrophe, such as in the case of gastrointestinal stromal tumors or chronic myeloid leukemia. In other words, the separation and isolation of the driver from the passengers is required to improve accuracy in cancer treatment. This review will summarize the signaling pathway crossroads that govern renal cell carcinoma proliferation and the emerging understanding of how these pathways facilitate tumor escape. We outline the available evidence supporting the putative links between different signaling pathways and how they may influence tumor proliferation, differentiation, apoptosis, angiogenesis, metabolism and invasiveness. The conclusion is that tumor cells may generate their own crossroads/crosstalk among signaling pathways, thereby reducing their dependence on stimulation of their physiologic pathways.
    Preview · Article · Dec 2012 · International Journal of Molecular Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: In the last several years, researchers have exhibited an intense interest in the evolutionarily conserved signaling pathways that have crucial roles during embryonic development. Interestingly, the malfunctioning of these signaling pathways leads to several human diseases, including cancer. The chemical and biophysical events that occur during cellular signaling, as well as the number of interactions within a signaling pathway, make these systems complex to study. In silico resources are tools used to aid the understanding of cellular signaling pathways. Systems approaches have provided a deeper knowledge of diverse biochemical processes, including individual metabolic pathways, signaling networks and genome-scale metabolic networks. In the future, these tools will be enormously valuable, if they continue to be developed in parallel with growing biological knowledge. In this study, an overview of the bioinformatics resources that are currently available for the analysis of biological networks is provided.
    Preview · Article · Dec 2012 · International Journal of Molecular Sciences
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    [Show abstract] [Hide abstract] ABSTRACT: Background Many studies have demonstrated genetic and environmental factors that lead to renal cell carcinoma (RCC) and that occur during a protracted period of tumourigenesis. It appears suitable to identify and characterise potential molecular markers that appear during tumourigenesis and that might provide rapid and effective possibilities for the early detection of RCC. EGFR activation induces cell cycle progression, inhibition of apoptosis and angiogenesis, promotion of invasion/metastasis, and other tumour promoting activities. Over-expression of EGFR is thought to play an important role in tumour initiation and progression of RCC because up-regulation of EGFR has been associated with high grade cancers and a worse prognosis. Methods Characterisation of the protein profile interacting with EGFR was performed using the following: an immunohistochemical (IHC) study of EGFR, a comprehensive computational study of EGFR protein-protein interactions, an analysis correlating the expression levels of EGFR with other significant markers in the tumourigenicity of RCC, and finally, an analysis of the utility of EGFR for prognosis in a cohort of patients with renal cell carcinoma. Results The cases that showed a higher level of this protein fell within the clear cell histological subtype (p = 0.001). The EGFR significance statistic was found with respect to a worse prognosis. In vivo significant correlations were found with PDGFR-β, Flk-1, Hif1-α, proteins related to differentiation (such as DLL3 and DLL4 ligands), and certain metabolic proteins such as Glut5. In silico significant associations gave us a panel of 32 EGFR-interacting proteins (EIP) using the APID and STRING databases. Conclusions This work summarises the multifaceted role of EGFR in the pathology of RCC, and it identifies EIPs that could help to provide mechanistic explanations for the different behaviours observed in tumours.
    Preview · Article · Sep 2012 · Journal of Molecular Signaling

Publication Stats

362 Citations
198.72 Total Impact Points

Institutions

  • 2007-2012
    • University of A Coruña
      • Department of Medicine
      La Corogne, Galicia, Spain
  • 2011
    • Complejo Hospitalario Universitario a Coruña (CHUAC)
      La Corogne, Galicia, Spain
  • 2009-2010
    • Complexo Hospitalario Universitario A Coruña
      La Corogne, Galicia, Spain