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Pancreatic ductal adenocarcinoma (PDAC) represents the most prevalent type of pancreatic cancer and ranks among the most aggressive tumours, with a 5-year survival rate of less than 11%. Projections indicate that by 2030, it will become the second leading cause of cancer-related deaths. PDAC presents distinctive hallmarks contributing to its dismal prognosis: (i) late diagnosis, (ii) heterogenous and complex mutational landscape, (iii) high metastatic potential, (iv) dense fibrotic stroma, (v) immunosuppressive microenvironment, and (vi) high resistance to therapy. Mounting evidence has shown a role for TAM (Tyro3, AXL, MerTK) family of tyrosine kinase receptors in PDAC initiation and progression. This review aims to describe the impact of TAM receptors on the defining hallmarks of PDAC and discuss potential future directions using these proteins as novel biomarkers for early diagnosis and targets for precision therapy in PDAC, an urgent unmet clinical need.
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Targeting phospholipid biosynthesis, specifically phosphatidylcholine (PC), which is enhanced in tumor cells, has been proven a suitable antitumor strategy. In fact, the overexpression of the choline kinase α1 (ChoKα1) isoform has been found in malignant cells and tumors, thus becoming an excellent antitumor target. ChoKα1 inhibitors are being synthesized at the present that show a large inhibitory activity. Two of them have been chosen in this study as representatives of different structural families: a biscationic biphenyl derivative of thieno[3,2-d]pyrimidinium substituted with a cyclic amine (here referred to as Fa22) and a biscationic biphenyl thioethano derivative of 7-chloro-quinolinium substituted with a pyrrolidinic moiety (here referred to as PL48). However, the potential use of these types of compounds in systemic treatments is hampered because of their low specificity. In fact, to enter the cell and reach their target, these inhibitors use choline transporters and inhibit choline uptake, being that one of the causes of their toxicity. One way to solve this problem could be allowing their entrance into the cells by alternative ways. With this goal, MamC-mediated magnetic nanoparticles (BMNPs), already proven effective drug nanocarriers, have been used to immobilize Fa22 and PL48. The idea is to let BMNPs enter the cell (they enter the cell by endocytosis) carrying these molecules, and, therefore, offering another way in for these compounds. In the present study, we demonstrate that the coupling of Fa22 and PL48 to BMNPs allows these molecules to enter the tumoral cell without completely inhibiting choline uptake, so, therefore, the use of Fa22 and PL48 in these nanoformulations reduces the toxicity compared to that of the soluble drugs. Moreover, the nanoassemblies Fa22-BMNPs and PL48-BMNPs allow the combination of chemotherapy and local hyperthermia therapies for a enhanced cytotoxic effect on the tumoral HepG2 cell line. The consistency of the results, independently of the drug structure, may indicate that this behavior could be extended to other ChoKα1 inhibitors, opening up a possibility for their potential use in clinics.
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Metastatic colorectal cancer (mCRC) currently lacks reliable biomarkers for precision medicine, particularly for chemotherapy-based treatments. This study examines the behavior of 11 CXC chemokines in the blood of 104 mCRC patients undergoing first-line oxaliplatin-based treatment to pinpoint predictive and prognostic markers. Serum samples were collected before treatment, at response evaluation (EVAR), and at disease progression or last follow-up. Chemokines were assessed in all samples using a Luminex® custom panel. CXCL13 levels increased at EVAR in responders, while in non-responders it decreased. Increasing levels of CXCL13 at EVAR, independently correlated with improved progression-free survival (PFS) and overall survival (OS). Nanostring® analysis in primary tumor samples showed CXCL13 gene expression's positive correlation not only with gene profiles related to an immunogenic tumor microenvironment, increased B cells and T cells (mainly CD8+) but also with extended OS. In silico analysis using RNAseq data from liver metastases treated or not with neoadjuvant oxaliplatin-based combinations, and deconvolution analysis using the MCP-counter algorithm, confirmed CXCL13 gene expression's association with increased immune infiltration, improved OS, and Tertiary Lymphoid Structures (TLSs) gene signatures, especially in neoadjuvant-treated patients. CXCL13 analysis in serum from 36 oxaliplatin-treated patients from the METIMMOX study control arm, reported similar findings. In conclusion, the increase of CXCL13 levels in peripheral blood and its association with the formation of TLSs within the metastatic lesions, emerges as a potential biomarker indicative of the therapeutic efficacy in mCRC patients undergoing oxaliplatin-based treatment.
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Biomarcadores Tumorais , Quimiocina CXCL13 , Neoplasias Colorretais , Oxaliplatina , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Oxaliplatina/uso terapêutico , Oxaliplatina/farmacologia , Masculino , Quimiocina CXCL13/sangue , Feminino , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/sangue , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Microambiente Tumoral , PrognósticoRESUMO
BACKGROUND: It is unclear whether optimising intraoperative cardiac index can reduce postoperative complications. We tested the hypothesis that maintaining optimised postinduction cardiac index during and for the first 8 h after surgery reduces the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. METHODS: In three German and two Spanish centres, high-risk patients having elective major open abdominal surgery were randomised to cardiac index-guided therapy to maintain optimised postinduction cardiac index (cardiac index at which pulse pressure variation was <12%) during and for the first 8 h after surgery using intravenous fluids and dobutamine or to routine care. The primary outcome was the incidence of a composite outcome of moderate or severe complications within 28 days after surgery. RESULTS: We analysed 318 of 380 enrolled subjects. The composite primary outcome occurred in 84 of 152 subjects (55%) assigned to cardiac index-guided therapy and in 77 of 166 subjects (46%) assigned to routine care (odds ratio: 1.87, 95% confidence interval: 1.03-3.39, P=0.038). Per-protocol analyses confirmed the results of the primary outcome analysis. CONCLUSIONS: Maintaining optimised postinduction cardiac index during and for the first 8 h after surgery did not reduce, and possibly increased, the incidence of a composite outcome of complications within 28 days after surgery compared with routine care in high-risk patients having elective major open abdominal surgery. Clinicians should not strive to maintain optimised postinduction cardiac index during and after surgery in expectation of reducing complications. CLINICAL TRIAL REGISTRATION: NCT03021525.
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Abdome , Complicações Pós-Operatórias , Humanos , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/epidemiologia , Abdome/cirurgia , Débito Cardíaco , Dobutamina/administração & dosagem , Hidratação/métodos , Idoso de 80 Anos ou mais , Monitorização Intraoperatória/métodos , Cardiotônicos/uso terapêutico , Cardiotônicos/administração & dosagem , Procedimentos Cirúrgicos Eletivos/efeitos adversosRESUMO
Laparoscopy offers numerous advantages over open procedures, minimizing trauma, reducing pain, accelerating recovery, and shortening hospital stays. Despite other technical advancements, pneumoperitoneum insufflation has received little attention, barely evolving since its inception. We explore the impact of pneumoperitoneum on patient outcomes and advocate for a minimally invasive approach that prioritizes peritoneal homeostasis. The nonlinear relationship between intra-abdominal pressure (IAP) and intra-abdominal volume (IAV) is discussed, emphasizing IAP titration to balance physiological effects and surgical workspace. Maintaining IAP below 10 mmHg is generally recommended, but factors such as patient positioning and surgical complexity must be considered. The depth of neuromuscular blockade (NMB) is explored as another variable affecting laparoscopic conditions. While deep NMB appears favorable for surgical stillness, achieving a balance between IAP and NMB depth is crucial. Temperature and humidity management during pneumoperitoneum are crucial for patient safety and optical field quality. Despite the debate over the significance of temperature drop, humidification and the warming of insufflated gas offer benefits in peritoneal homeostasis and visual clarity. In conclusion, there is potential for a paradigm shift in pneumoperitoneum management, with dynamic IAP adjustments and careful control of insufflated gas temperature and humidity to preserve peritoneal homeostasis and improve patient outcomes in minimally invasive surgery.
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Eosinophilic esophagitis (EoE) is a chronic, progressive, type 2 inflammatory disease with increasing global prevalence. An eosinophil-predominant inflammation that permeates the epithelium and deeper esophageal layers characterizes the disease. Several cytokines, mainly derived from inflammatory T-helper 2 (Th2) cells and epithelial cells, are involved in perpetuating inflammatory responses by increasing surface permeability and promoting tissue remodeling characterized by epithelial-mesenchymal transition (EMT) and collagen deposition. This leads to esophageal strictures and narrow caliber esophagi, which are proportional a patient's age and untreated disease length. Pathophysiological mechanisms leading to EoE have been described in recent years, and transforming growth factor beta (TGF)-beta have been involved in fibrotic phenomena in EoE. However, evidence on the dependence of these phenomena on TGF-beta is scarce and contradictory. This review provides state-of-the art knowledge on intimate mechanisms of esophageal fibrosis in EoE and its clinical consequences.
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Esofagite Eosinofílica , Humanos , Citocinas , Células Epiteliais , Transição Epitelial-Mesenquimal , EpitélioRESUMO
Glioblastoma (GBM) is the most frequent primary malignant brain tumor and has a dismal prognosis. Unfortunately, despite the recent revolution of immune checkpoint inhibitors in many solid tumors, these have not shown a benefit in overall survival in GBM patients. Therefore, new potential treatment targets as well as diagnostic, prognostic, and/or predictive biomarkers are needed to improve outcomes in this population. The ß-galactoside binding protein Galectin-1 (Gal-1) is a protein with a wide range of pro-tumor functions such as proliferation, invasion, angiogenesis, and immune suppression. Here, we evaluated Gal-1 expression by immunohistochemistry in a homogenously treated cohort of GBM (the GLIOCAT project) and correlated its expression with clinical and molecular data. We observed that Gal-1 is a negative prognostic factor in GBM. Interestingly, we observed higher levels of Gal-1 expression in the mesenchymal/classical subtypes compared to the less aggressive proneural subtype. We also observed a Gal-1 expression correlation with immune suppressive signatures of CD4 T-cells and macrophages, as well as with several GBM established biomarkers, including SHC1, PD-L1, PAX2, MEOX2, YKL-40, TCIRG1, YWHAG, OLIG2, SOX2, Ki-67, and SOX11. Moreover, Gal-1 levels were significantly lower in grade 4 IDH-1 mutant astrocytomas, which have a better prognosis. Our results confirm the role of Gal-1 as a prognostic factor and also suggest its value as an immune-suppressive biomarker in GBM.
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Astrocitoma , Glioblastoma , ATPases Vacuolares Próton-Translocadoras , Humanos , Galectina 1/genética , Galectina 1/metabolismo , Prognóstico , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/metabolismo , Astrocitoma/metabolismo , Biomarcadores , ATPases Vacuolares Próton-Translocadoras/metabolismo , Proteínas 14-3-3/metabolismoRESUMO
A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.
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Antineoplásicos , Fibroblastos Associados a Câncer , Neoplasias Colorretais , Humanos , Fibroblastos Associados a Câncer/patologia , Oxaliplatina/farmacologia , Distribuição Tecidual , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Microambiente Tumoral , Fibroblastos/patologia , Linhagem Celular TumoralRESUMO
Since the identification of human choline kinase as a protein target against cancer progression, many compounds have been designed to inhibit its function and reduce the biosynthesis of phosphatidylcholine. Herein, we propose a series of bioisosteric inhibitors that are based on the introduction of sulphur and feature improved activity and lipophilic/hydrophilic balance. The evaluation of the inhibitory and of the antiproliferative properties of the PL (dithioethane) and FP (disulphide) libraries led to the identification of PL 48, PL 55 and PL 69 as the most active compounds of the series. Docking analysis using FLAP suggests that for hits to leads, binding mostly involves an interaction with the Mg2+ cofactor, or its destabilization. The most active compounds of the two series are capable of inducing apoptosis following the mitochondrial pathway and to significantly reduce the expression of anti-apoptotic proteins such as the Mcl-1. The fluorescence properties of the compounds of the PL library allowed the tracking of their mode of action, while PAINS (Pan Assays Interference Structures) filtration databases suggest the lack of any unspecific biological response.
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Antineoplásicos , Neoplasias , Humanos , Colina/metabolismo , Colina/farmacologia , Colina Quinase , Proliferação de Células , Antineoplásicos/química , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Hypersialylation is a feature of pancreatic ductal adenocarcinoma (PDA) and it has been related to tumor malignancy and immune suppression. In this work, we have evaluated the potential of the sialyltransferase inhibitor, Ac53FaxNeu5Ac, to decrease tumor sialoglycans in PDA and to revert its malignant phenotype. Sialoglycans on PDA cells were evaluated by flow cytometry, and the functional impact of Ac53FaxNeu5Ac was assessed using E-selectin adhesion, migration, and invasion assays. PDA tumors were generated in syngeneic mice from KC cells and treated with Ac53FaxNeu5Ac to evaluate tumor growth, mice survival, and its impact on blocking sialic acid (SA) and on the tumor immune component. Ac53FaxNeu5Ac treatment on human PDA cells decreased α2,3-SA and sialyl-Lewisx, which resulted in a reduction in their E-selectin adhesion, and in their migratory and invasive capabilities. Subcutaneous murine tumors treated with Ac53FaxNeu5Ac reduced their volume, their SA expression, and modified their immune component, with an increase in CD8+ T-lymphocytes and NK cells. In conclusion, Ac53FaxNeu5Ac treatment weakened PDA cells' malignant phenotype, thereby reducing tumor growth while favoring anti-tumor immune surveillance. Altogether, these results show the positive impact of reducing SA expression by inhibiting cell sialyltransferases and open the way to use sialyltransferase inhibitors to target this dismal disease.
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Low-grade systemic inflammation is associated with a range of conditions. Diet may modulate inflammation and public health strategies are needed to guide consumers' dietary choices and help prevent diet-related disease. The Food Standards Agency nutrient profiling system (FSAm-NPS) constitutes the basis of the five-colour front-of-pack Nutri-Score labelling system. No study to date has examined FSAm-NPS dietary index associations with biomarkers of inflammation. Therefore, our objective was to test relationships between the FSAm-NPS and a range of inflammatory biomarkers in a cross-sectional sample of 2006 men and women aged 46-73 years. Individual participant FSAm-NPS scores were derived from food frequency questionnaires. Pro-inflammatory cytokine, adipocytokine, acute-phase response protein, coagulation factor and white blood cell count concentrations were determined. Correlation and linear regression analyses were used to examine FSAm-NPS relationships with biomarker levels. In crude and adjusted analyses, higher FSAm-NPS scores, reflecting poorer nutritional quality, were consistently and positively associated with biomarkers. In fully adjusted models, significant associations with concentrations of complement component 3, c-reactive protein, interleukin 6, tumour necrosis factor alpha, resistin, white blood cell count, neutrophils, eosinophils and the neutrophil-to-lymphocyte ratio persisted. These results suggest that dietary quality, determined by Nutri-Score rating, is associated with inflammatory biomarkers related to health.
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Rotulagem de Alimentos , Preferências Alimentares , Idoso , Biomarcadores , Estudos Transversais , Feminino , Rotulagem de Alimentos/métodos , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Nutrientes , Valor NutritivoRESUMO
PURPOSE: To assess relationships between the Dietary Approaches to Stop Hypertension (DASH), Mediterranean Diet (MD), Dietary Inflammatory Index (DII®) and Energy-adjusted DII (E-DII™) scores and pro-inflammatory cytokines, adipocytokines, acute-phase response proteins, coagulation factors and white blood cells. METHODS: This was a cross-sectional study of 1862 men and women aged 46-73 years, randomly selected from a large primary care centre in Ireland. DASH, MD, DII and E-DII scores were derived from validated food frequency questionnaires. Correlation and multivariate-adjusted linear regression analyses with correction for multiple testing were performed to examine dietary score relationships with biomarker concentrations. RESULTS: In fully adjusted models, higher diet quality or a less pro-inflammatory diet was associated with lower concentrations of c-reactive protein, neutrophils (all dietary scores), complement component 3 [C3], interleukin 6 [IL-6], tumour necrosis factor-alpha [TNF-α], white blood cell count [WBC], the neutrophil-to-lymphocyte ratio [NLR] (DASH, DII and E-DII), monocytes (DASH and DII) and resistin (DII and E-DII). After accounting for multiple testing, relationships with C3 (DASH: ß = - 2.079, p = .011 and DII: ß = 2.521, p = .036), IL-6 (DASH: ß = - 0.063, p = .011), TNF-α (DASH: ß = - 0.027, p = .034), WBC (DASH: ß = - 0.028, p = .001 and DII: ß = 0.029, p = .02), neutrophils (DASH: ß = - 0.041, p = .001; DII: ß = 0.043, p = .007; E-DII: ß = 0.029, p = .009) and the NLR (DASH: ß = - 0.035, p = .011) persisted. CONCLUSIONS: Better diet quality, determined by the DASH score, may be more closely associated with inflammatory biomarkers related to health in middle- to older-aged adults than the MD, DII and E-DII scores.
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Interleucina-6 , Fator de Necrose Tumoral alfa , Idoso , Biomarcadores , Estudos Transversais , Dieta , Feminino , Humanos , Inflamação , Masculino , Pessoa de Meia-IdadeRESUMO
Due to its role in lipid biosynthesis, choline kinase α1 (CKα1) is an interesting target for the development of new antitumor agents. In this work, we present a series of 41 compounds designed based on the well-known and successful strategy of introducing thienopyridine and pyrimidine as bioisosteres of other heterocycles in active antitumor compounds. Notwithstanding the fact that some of these compounds do not show significant enzymatic inhibition, others, in contrast, feature substantially improved enzymatic and antiproliferative inhibition values. This is also confirmed by docking analysis, whereby compounds with longer linkers and thienopyrimidine cationic head have been identified as the most compelling. Among the best compounds is Ff-35, which inhibits the growth of different tumor cells at submicromolar concentrations. Moreover, Ff-35 is more potent in inhibiting CKα1 than other previous biscationic derivatives. Treatment of A549, Hela, and MDA-MB-231 cells with Ff-35 results in their arrest at the G1 phase of the cell cycle. Furthermore, the compound induces cellular apoptosis in a concentration-dependent manner. Altogether, these findings indicate that Ff-35 is a promising new chemotherapeutic agent with encouraging preclinical potential.
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Introduction: Objective: the objective of our study was to evaluate the level of understanding of ostomy patients regarding lifestyle, diet, and high output stoma (HOS) management recommendations provided by healthcare professionals. Method: a prospective study to follow up ostomy patients at nutritional consultations was designed. The follow-up process was performed 7-10 days after hospital discharge and again one month later. At the first visit, patients were instructed in the detection and management of HOS. At the second visit, the level of understanding of the training received was assessed using an evaluation questionnaire. A descriptive analysis of the answers to each of the questionnaire's items was performed. Fisher's exact test was used to evaluate differences in the level of understanding recorded with the questionnaire. Results: a total of 35 patients were recruited; 71.4 % did not provide correct answers to all the questions. There were no significant differences in the correctness of the answers to the questionnaire according to education level. Conclusions: many patients do not adequately understand the information provided by healthcare professionals and this could have a negative impact on the incidence of clinical complications.
Introducción: Objetivo: el objetivo de nuestro estudio fue evaluar el nivel de comprensión de los pacientes ostomizados con respecto a las recomendaciones sobre estilo de vida, dieta y manejo de la ostomía de alto débito (OAD) proporcionadas por los profesionales de la salud. Método: se diseñó un estudio prospectivo para el seguimiento de pacientes ostomizados en consulta de nutrición. El seguimiento se realizó 7-10 días después del alta hospitalaria y a continuación un mes después. En la primera visita, se instruyó a los pacientes sobre la detección y el tratamiento de OAD. En la segunda visita se evaluó el nivel de comprensión de la formación recibida mediante un cuestionario de evaluación. Se registraron las respuestas dadas a cada uno de los ítems del cuestionario y se realizó un análisis descriptivo. Para evaluar las diferencias en el nivel de comprensión registrado con el cuestionario se utilizó la prueba exacta de Fisher. Resultados: se reclutaron 35 pacientes. El 71,4 % no respondieron correctamente a todas las preguntas. La exactitud de las respuestas al cuestionario no mostró diferencias significativas según el nivel educativo. Conclusiones: un gran número de pacientes no comprende adecuadamente la información que ofrecen los profesionales sanitarios y esto podría tener un impacto negativo en el desarrollo de complicaciones clínicas.
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Estomia , Dieta , Humanos , Estilo de Vida , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
Galectins have been linked to tumorigenesis since 1975, even before this family of proteins was given its name. Since then, hundreds of papers have analyzed the role of different galectins in cancer development and progression, deciphering their involvement in many different pathological events, from the regulation of cell cycle, to angiogenesis, metastasis, and immune attack evasion. Importantly, the tumor galectin profile is often altered in many cancers and aberrant levels of some of the members of this family have been considered in diagnosis and frequently correlated with patient prognosis and clinicopathological characteristics. In this chapter, we summarize most frequent techniques employed in cancer research to interrogate the role of galectins, using Gal-1 to illustrate one member of the family and pancreatic cancer as an experimental model. We will cover from techniques employed to detect their expression (tissue and blood samples) to the most frequent tools used to change expression levels and the cell line-based in vitro studies and murine preclinical models used to explore their role in tumor progression and/or clinical translation.
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Galectinas , Neoplasias Pancreáticas , Animais , Carcinogênese , Transformação Celular Neoplásica , Galectinas/genética , Galectinas/metabolismo , Humanos , Camundongos , Neoplasias Experimentais/metabolismo , Neoplasias Pancreáticas/metabolismoRESUMO
Dyslipidemia, metabolic disorders and/or obesity are postulated as risk factors for pancreatic ductal adenocarcinoma (PDAC). The majority of patients with these metabolic alterations have low density lipoproteins (LDLs) with increased susceptibility to become aggregated in the extracellular matrix (ECM). LDL aggregation can be efficiently inhibited by low-density lipoprotein receptor-related protein 1 (LRP1)-based peptides. The objectives of this work were: (i) to determine if aggregated LDLs affect the intracellular cholesteryl ester (CE)/free cholesterol (FC) ratio and/or the tumor pancreatic cell proliferation, using sphingomyelinase-modified LDL particles (Aggregated LDL, AgLDL); and (ii) to test whether LRP1-based peptides, highly efficient against LDL aggregation, can interfere in these processes. For this, we exposed human pancreatic cancer cell lines (PANC-1, RWP-1 and Capan-1) to native (nLDL) or AgLDLs in the absence or presence of LRP1-based peptides (DP3) or irrelevant peptides (IP321). Results of thin-layer chromatography (TLC) following lipid extraction indicate that AgLDLs induce a higher intracellular CE/FC ratio than nLDL, and that DP3 but not IP321 counteracts this effect. AgLDLs also increase PANC-1 cell proliferation, which is inhibited by the DP3 peptide. Our results indicate that AgLDL-induced intracellular CE accumulation plays a crucial role in the proliferation of pancreatic tumor cell lines. Peptides with anti-LDL aggregation properties may thus exhibit anti-tumor effects.
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A large number of different types of cancer have been shown to be associated with an abnormal metabolism of phosphatidylcholine (PC), the main component of eukaryotic cell membranes. Indeed, the overexpression of choline kinase α1 (ChoKα1), the enzyme that catalyses the bioconversion of choline to phosphocholine (PCho), has been found to associate with cell proliferation, oncogenic transformation and carcinogenesis. Hence, ChoKα1 has been described as a possible cancer therapeutic target. Moreover, the choline transporter CTL1 has been shown to be highly expressed in several tumour cell lines. In the present work, we evaluate the antiproliferative effect of PL48, a rationally designed inhibitor of ChoKα1, in MCF7 and HepG2 cell lines. In addition, we illustrate that the predominant mechanism of cellular choline uptake in these cells is mediated by the CTL1 choline transporter. A possible correlation between the inhibition of both choline uptake and ChoKα1 activity and cell proliferation in cancer cell lines is also highlighted. We conclude that the efficacy of this inhibitor on cell proliferation in both cell lines is closely correlated with its capability to block choline uptake and ChoKα1 activity, making both proteins potential targets in cancer therapy.
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BACKGROUND: Early diagnosis is crucial for patients with pancreatic ductal adenocarcinoma (PDAC). The AXL receptor tyrosine kinase is proteolytically processed releasing a soluble form (sAXL) into the blood stream. Here we explore the use of sAXL as a biomarker for PDAC. METHODS: AXL was analysed by immunohistochemistry in human pancreatic tissue samples. RNA expression analysis was performed using TCGA/GTEx databases. The plasma concentrations of sAXL, its ligand GAS6, and CA19-9 were studied in two independent cohorts, the HMar cohort (n = 59) and the HClinic cohort (n = 142), including healthy controls, chronic pancreatitis (CP) or PDAC patients, and in a familial PDAC cohort (n = 68). AXL expression and sAXL release were studied in PDAC cell lines and murine models. FINDINGS: AXL is increased in PDAC and precursor lesions as compared to CP or controls. sAXL determined in plasma from two independent cohorts was significantly increased in the PDAC group as compared to healthy controls or CP patients. Patients with high levels of AXL have a lower overall survival. ROC analysis of the plasma levels of sAXL, GAS6, or CA19-9 in our cohorts revealed that sAXL outperformed CA19-9 for discriminating between CP and PDAC. Using both sAXL and CA19-9 increased the diagnostic value. These results were validated in murine models, showing increased sAXL specifically in animals developing PDAC but not those with precursor lesions or acinar tumours. INTERPRETATION: sAXL appears as a biomarker for early detection of PDAC and PDAC-CP discrimination that could accelerate treatment and improve its dismal prognosis. FUNDING: This work was supported by grants PI20/00625 (PN), RTI2018-095672-B-I00 (AM and PGF), PI20/01696 (MG) and PI18/01034 (AC) from MICINN-FEDER and grant 2017/SGR/225 (PN) from Generalitat de Catalunya.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Pancreatite Crônica , Animais , Biomarcadores Tumorais , Antígeno CA-19-9 , Carcinoma Ductal Pancreático/diagnóstico , Diagnóstico Diferencial , Diagnóstico Precoce , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos , Neoplasias Pancreáticas/diagnóstico , Pancreatite Crônica/diagnósticoRESUMO
Dysregulation of the c-Myc oncogene occurs in a wide variety of hematologic malignancies, and its overexpression has been linked with aggressive tumor progression. Here, we show that poly (ADP-ribose) polymerase 1 (PARP-1) and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphoma. PARP-1 and PARP-2 catalyze the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphoma, whereas PARP-1 deficiency accelerates lymphomagenesis in the Eµ-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in preleukemic Eµ-Myc B cells, resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1 deficiency induces a proinflammatory response and an increase in regulatory T cells, likely contributing to immune escape of B-cell lymphoma, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centered therapeutic strategies, with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumors.