RESUMEN
Mesothelial and epicardial cells give rise to various types of mesenchymal cells via epithelial (mesothelial)-to-mesenchymal transition during development. However, the genes controlling the differentiation and diversification of mesothelial/epicardial cells remain unclear. Here, we examined Wnt2b expression in the embryonic mesothelium and epicardium and performed lineage tracing of Wnt2b-expressing cells by using novel Wnt2b-2A-CreERT2 knock-in and LacZ-reporter mice. Wnt2b was expressed in mesothelial cells covering visceral organs, but the expression was restricted in their subpopulations. Wnt2b-expressing cells labeled at embryonic day (E) 10.5 were distributed to the mesothelium and mesenchyme in the lungs, abdominal wall, stomach, and spleen in Wnt2b2A-CreERT2/+;R26RLacZ/+ mice at E13.0. Wnt2b was initially expressed in the proepicardial organ (PEO) at E9.5 and then in the epicardium after E10.0. Wnt2b-expressing PEO cells labeled at E9.5 differentiated into a small fraction of cardiac fibroblasts and preferentially localized at the left side of the postnatal heart. LacZ+ epicardium-derived cells labeled at E10.5 differentiated into a small fraction of fibroblasts and smooth muscle cells in the postnatal heart. Taken together, our results reveal novel subpopulations of PEO and mesothelial/epicardial cells that are distinguishable by Wnt2b expression and elucidate the unique contribution of Wnt2b-expressing PEO and epicardial cells to the postnatal heart.
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Cancer cells inevitably interact with neighboring host tissue-resident cells during the process of metastatic colonization, establishing a metastatic niche to fuel their survival, growth, and invasion. However, the underlying mechanisms in the metastatic niche are yet to be fully elucidated owing to the lack of methodologies for comprehensively studying the mechanisms of cell-cell interactions in the niche. Here, we improve a split green fluorescent protein (GFP)-based genetically encoded system to develop secretory glycosylphosphatidylinositol-anchored reconstitution-activated proteins to highlight intercellular connections (sGRAPHIC) for efficient fluorescent labeling of tissue-resident cells that neighbor on and putatively interact with cancer cells in deep tissues. The sGRAPHIC system enables the isolation of metastatic niche-associated tissue-resident cells for their characterization using a single-cell RNA sequencing platform. We use this sGRAPHIC-leveraged transcriptomic platform to uncover gene expression patterns in metastatic niche-associated hepatocytes in a murine model of liver metastasis. Among the marker genes of metastatic niche-associated hepatocytes, we identify Lgals3, encoding galectin-3, as a potential pro-metastatic factor that accelerates metastatic growth and invasion.
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Neoplasias Hepáticas , Humanos , Ratones , Animales , Neoplasias Hepáticas/metabolismo , Hepatocitos/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Matriz Extracelular/metabolismo , Comunicación CelularRESUMEN
Oxygen is essential for living organisms. Molecular oxygen binds to hemoglobin and is delivered to every organ in the body. In several cardiovascular diseases or anemia, local oxygen tension drops below its physiological level and tissue hypoxia develops. In such conditions, the expression of hypoxia-responsive genes increases to alleviate the respective condition. The hypoxia-responsive genes include the genes coding erythropoietin (EPO), vascular endothelial growth factor-A, and glycolytic enzymes. Hypoxia-inducible factor (HIF)-1α, HIF-2α, and HIF-3α are transcription factors that regulate the hypoxia-responsive genes. The HIF-α proteins are continuously degraded by an oxygen-dependent degrading pathway involving HIF-prolyl hydroxylases (HIF-PHs) and von Hippel-Lindau tumor suppressor protein. However, upon hypoxia, this degradation ceases and the HIF-α proteins form heterodimers with HIF-1ß (a constitutive subunit of HIF), which results in the induction of hypoxia responsive genes. HIF-1α and HIF-2α are potential therapeutic targets for renal anemia, where EPO production is impaired due to chronic kidney diseases. Small molecule HIF-PH inhibitors are currently used to activate HIF-α signaling and to increase plasma hemoglobin levels by restoring EPO production. In this review, we will discuss the current understanding of the roles of the HIF-α signaling pathway in cardiovascular diseases. This will include the roles of HIF-1α in cardiomyocytes as well as in stromal cells including macrophages.
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Enfermedades Cardiovasculares , Subunidad alfa del Factor 1 Inducible por Hipoxia , Humanos , Anemia/etiología , Hipoxia , Oxígeno , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
Fibrosis is the final path of nearly every form of chronic disease, regardless of the pathogenesis. Upon chronic injury, activated, fibrogenic fibroblasts deposit excess extracellular matrix, and severe tissue fibrosis can occur in virtually any organ. However, antifibrotic therapies that target fibrogenic cells, while sparing homeostatic fibroblasts in healthy tissues, are limited. We tested whether specific immunization against endogenous proteins, strongly expressed in fibrogenic cells but highly restricted in quiescent fibroblasts, can elicit an antigen-specific cytotoxic T cell response to ameliorate organ fibrosis. In silico epitope prediction revealed that activation of the genes Adam12 and Gli1 in profibrotic cells and the resulting "self-peptides" can be exploited for T cell vaccines to ablate fibrogenic cells. We demonstrate the efficacy of a vaccination approach to mount CD8+ T cell responses that reduce fibroblasts and fibrosis in the liver and lungs in mice. These results provide proof of principle for vaccination-based immunotherapies to treat fibrosis.
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Fibroblastos , Pulmón , Animales , Epítopos/metabolismo , Fibroblastos/metabolismo , Fibrosis , Inmunoterapia , Hígado/patología , Pulmón/metabolismo , Ratones , Vacunación , Proteína con Dedos de Zinc GLI1/metabolismoRESUMEN
Mutational activation of the KRAS gene occurs in almost all pancreatic ductal adenocarcinoma (PDAC) and is the earliest molecular event in their carcinogenesis. Evidence has accumulated of the metabolic reprogramming in PDAC, such as amino acid homeostasis and autophagic flux. However, the biological effects of KRAS mutation on metabolic reprogramming at the earlier stages of PDAC carcinogenesis are unclear. Here we report dynamic metabolic reprogramming in immortalized human non-cancerous pancreatic ductal epithelial cells, in which a KRAS mutation was induced by gene-editing, which may mimic early pancreatic carcinogenesis. Similar to the cases of PDAC, KRAS gene mutation increased the dependency on glucose and glutamine for maintaining the intracellular redox balance. In addition, the intracellular levels of amino acids were significantly decreased because of active protein synthesis, and the cells required greater autophagic flux to maintain their viability. The lysosomal inhibitor chloroquine significantly inhibited cell proliferation. Therefore, metabolic reprogramming is an early event in carcinogenesis initiated by KRAS gene mutation, suggesting a rationale for the development of nutritional interventions that suppress or delay the development of PDAC.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas p21(ras) , Carcinogénesis , Carcinoma Ductal Pancreático/metabolismo , Humanos , Mutación , Neoplasias Pancreáticas/patología , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Neoplasias PancreáticasRESUMEN
Significance: Magnetic resonance imaging (MRI) with hyperpolarized (HP) 13C-labeled redox-sensitive metabolic tracers can provide noninvasive functional imaging biomarkers, reflecting tissue redox state, oxidative stress, and inflammation, among others. The capability to use endogenous metabolites as 13C-enriched imaging tracers without structural modification makes HP 13C MRI a promising tool to evaluate redox state in patients with various diseases. Recent Advances: Recent studies have demonstrated the feasibility of in vivo metabolic imaging of 13C-labeled tracers polarized by parahydrogen-induced polarization techniques, which offer a cost-effective alternative to the more widely used dissolution dynamic nuclear polarization-based hyperpolarizers. Critical Issues: Although the fluxes of many metabolic pathways reflect the change in tissue redox state, they are not functionally specific. In the present review, we summarize recent challenges in the development of specific 13C metabolic tracers for biomarkers of redox state, including that for detecting reactive oxygen species. Future Directions: Applications of HP 13C metabolic MRI to evaluate redox state have only just begun to be investigated. The possibility to gain a comprehensive understanding of the correlations between tissue redox potential and metabolism under different pathological conditions by using HP 13C MRI is promoting its interest in the clinical arena, along with its noninvasive biomarkers to evaluate the extent of disease and treatment response.
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Imagen por Resonancia Magnética , Estrés Oxidativo , Humanos , Inflamación/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Oxidación-ReducciónRESUMEN
AIM: We explored the superiority of small dense low-density lipoprotein cholesterol (sdLDL-C) as a marker for predicting not only the occurrence of cardiovascular (CV) events but also the need for laser treatment in patients with hypercholesterolemia and diabetic retinopathy. METHODS: We performed a sub-analysis of the intEnsive statin therapy for hyper-cholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study (n=5042), in which patients were assigned randomly to intensive or standard statin therapy targeting low-density lipoprotein cholesterol ï¼70 mg/dl or 100-120 mg/dl. Using the survival analysis, the risks for CV events and the need for laser treatment were evaluated according to the lipids one year after registration. RESULTS: The patients were 63±11 years old. LDL-C and sdLDL-C levels were 98±25 and 32±14 mg/dl, respectively, one year after registration. The sdLDL-C level had a strong positive correlation with apolipoprotein B level (r=0.83 at registration). SdLDL-C was a sensitive marker for predicting CV events when comparing among the quartiles according to sdLDL-C levels (hazard ratios: HR for quartiles 1-4 were 1.0, 1.4, 1.6, and 2.5, respectively; p for trend ï¼0.01). Also, sdLDL-C was a sensitive marker for predicting the need for laser treatment among lipids (log rank, p=0.009), especially in patients with elderly (â§65 yrs) and obesity (BMI â§25 kg/m2). CONCLUSIONS: SdLDL-C is a sensitive target marker to predict cardiovascular events as well as the need for laser treatment in patients with hypercholesterolemia and diabetic retinopathy.
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Diabetes Mellitus , Retinopatía Diabética , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Anciano , Biomarcadores , LDL-Colesterol , Retinopatía Diabética/diagnóstico , Humanos , Rayos Láser , Persona de Mediana EdadAsunto(s)
Cardiomiopatía Restrictiva , Insuficiencia Cardíaca , Niño , Fibroblastos , Humanos , Miocitos CardíacosRESUMEN
Most seven transmembrane receptors (7TMRs) are G protein-coupled receptors; however, some 7TMRs evoke intracellular signals through ß-arrestin as a biased receptor. As several ß-arrestin-biased agonists have been reported to be cardioprotective, we examined the role of the chemokine receptor CXCR7 as a ß-arrestin-biased receptor in the heart. Among 510 7TMR genes examined, Cxcr7 was the most abundantly expressed in the murine heart. Single-cell RNA-sequencing analysis revealed that Cxcr7 was abundantly expressed in cardiomyocytes and fibroblasts. Cardiomyocyte-specific Cxcr7 null mice showed more prominent cardiac dilatation and dysfunction than control mice 4 weeks after myocardial infarction. In contrast, there was no difference in cardiac phenotypes between fibroblast-specific Cxcr7-knockout mice and control mice even after myocardial infarction. TC14012, a specific agonist of CXCR7, significantly recruited ß-arrestin to CXCR7 in CXCR7-expressing cells and activated extracellular signal-regulated kinase (ERK) in neonatal rat cardiomyocytes. Cxcr7 expression was significantly increased and ERK was activated in the border zone of the heart in control, but not Cxcr7 null mice. These results indicate that the abundantly expressed CXCR7 in cardiomyocytes may play a protective role in the heart as a ß-arrestin-biased receptor and that CXCR7 may be a novel therapeutic target for myocardial infarction.
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Sistema de Señalización de MAP Quinasas , Infarto del Miocardio/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Receptores CXCR/metabolismo , beta-Arrestina 1/metabolismo , Animales , Ratones , Ratones Noqueados , Infarto del Miocardio/genética , Infarto del Miocardio/patología , Miocardio/patología , Miocitos Cardíacos/patología , Oligopéptidos/farmacología , Receptores CXCR/agonistas , Receptores CXCR/genética , beta-Arrestina 1/genéticaRESUMEN
Patients with cardiovascular diseases frequently experience exertional dyspnea. However, the relationship between respiratory muscle strength including its fatigue and cardiovascular dysfunctions remains to be clarified.The maximal inspiratory pressure/maximal expiratory pressure (MIP/MEP) before and after cardiopulmonary exercise testing (CPX) in 44 patients with heart failure and ischemic heart disease were measured. Respiratory muscle fatigue was evaluated by calculating MIP (MIPpost/MIPpre) and MEP (MEPpost/MEPpre) changes.The mean MIPpre and MEPpre values were 67.5â±â29.0 and 61.6â±â23.8âcm H2O, respectively. After CPX, MIP decreased in 25 patients, and MEP decreased in 22 patients. We evaluated the correlation relationship between respiratory muscle function including respiratory muscle fatigue and exercise capacity evaluated by CPX such as peak VO2 and VE/VCO2 slope. Among MIP, MEP, change in MIP, and change in MEP, only the value of change in MIP had an association with the value of VE/VCO2 slope (R = -0.36, Pâ=â.017). In addition, multivariate analysis for determining factor of change in MIP revealed that the association between the change in MIP and eGFR was independent from other confounding parameters (beta, 0.40, Pâ=â.017). The patients were divided into 2 groups, with (MIP changeâ<â0.9) and without respiratory muscle fatigue (MIP changeâ>â0.9), and a significant difference in peak VO2 (14.2â±â3.4 [with fatigue] vs 17.4â±â4.7 [without fatigue] mL/kg/min; Pâ=â.020) was observed between the groups.Respiratory muscle fatigue demonstrated by the change of MIP before and after CPX significantly correlated with exercise capacity and renal function in patients with cardiovascular disease.
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Insuficiencia Cardíaca/fisiopatología , Fatiga Muscular , Isquemia Miocárdica/fisiopatología , Músculos Respiratorios/fisiopatología , Anciano , Ejercicio Físico/fisiología , Prueba de Esfuerzo , Tolerancia al Ejercicio , Femenino , Tasa de Filtración Glomerular , Humanos , Riñón/fisiopatología , Masculino , Presiones Respiratorias Máximas , Persona de Mediana EdadRESUMEN
BACKGROUND: Variants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking. METHODS: By CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome. RESULTS: A frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue. CONCLUSION: Our novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.
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Vasos Sanguíneos/patología , Miocardio/patología , Síndrome de Noonan/genética , Proteínas de Pez Cebra/genética , Alelos , Animales , Vasos Sanguíneos/metabolismo , Mutación con Pérdida de Función , Miocardio/metabolismo , Síndrome de Noonan/patología , Pez Cebra , Proteínas de Pez Cebra/metabolismoRESUMEN
Concomitant heart failure is associated with poor clinical outcome in dialysis patients. The arteriovenous shunt, created as vascular access for hemodialysis, increases ventricular volume-overload, predisposing patients to developing cardiac dysfunction. The integral function of mitochondrial respiration is critically important for the heart to cope with hemodynamic overload. The involvement, however, of mitochondrial activity or reactive oxygen species (ROS) in the pathogenesis of ventricular-overload-induced heart failure has not been fully elucidated. We herein report that disorganization of mitochondrial respiration increases mitochondrial ROS production in the volume-overloaded heart, leading to ventricular dysfunction. We adopted the murine arteriovenous fistula (AVF) model, which replicates the cardinal features of volume-overload-induced ventricular dysfunction. Enzymatic assays of cardiac mitochondria revealed that the activities of citrate synthase and NADH-quinone reductase (complex â ) were preserved in the AVF heart. In contrast, the activity of NADH oxidase supercomplex was significantly compromised, resulting in elevated ROS production. Importantly, the antioxidant N-acetylcysteine prevented the development of ventricular dilatation and cardiac dysfunction, suggesting a pathogenic role for ROS in dialysis-related cardiomyopathy. A cardioprotective effect was also observed in metformin-treated mice, illuminating its potential use in the management of heart failure complicating diabetic patients on dialysis.
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Acetilcisteína/uso terapéutico , Antioxidantes/uso terapéutico , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatías/etiología , Mitocondrias/metabolismo , Terapia Molecular Dirigida , Miocitos Cardíacos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Acetilcisteína/farmacología , Animales , Antioxidantes/farmacología , Cardiomiopatías/metabolismo , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Masculino , Ratones Endogámicos C57BLRESUMEN
Myocardial infarction (MI) occurs when the heart muscle is severely damaged due to a decrease in blood flow from the coronary arteries. During recovery from an MI, cardiac fibroblasts become activated and produce extracellular matrices, contributing to the wound healing process in the damaged heart. Inappropriate activation of the fibroblasts leads to excessive fibrosis in the heart. However, the molecular pathways by which cardiac fibroblasts are activated have not yet been fully elucidated.Here we show that serum deprivation, which recapitulates the cellular microenvironment of the MI area, strikingly induces collagen production in C3H/10T1/2 cells. Based on transcriptomic and pharmacological studies, we found that cell cycle perturbation is directly linked to collagen production in fibroblasts. Importantly, collagen synthesis is increased independently of the transcriptional levels of type I collagen genes. These results reveal a novel mode of fibroblast activation in the ischemic area, which will allow us to gain insights into the molecular mechanisms underlying cardiac fibrosis and establish a basis for anti-fibrotic therapy.
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Colágeno/biosíntesis , Infarto del Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Ciclo Celular , Células Cultivadas , Fibroblastos/metabolismo , Ratones , Infarto del Miocardio/patología , Miocitos Cardíacos/patología , Transducción de SeñalRESUMEN
The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-ß1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-ß1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-ß1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.
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Fibrosis/metabolismo , Hipoxia/metabolismo , Macrófagos/metabolismo , Oncostatina M/metabolismo , Animales , Antígenos Ly/genética , Antígenos Ly/metabolismo , Femenino , Fibroblastos/metabolismo , Fibrosis/genética , Fibrosis/patología , Hipoxia/genética , Hipoxia/patología , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa 1 Activada por Mitógenos/genética , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/genética , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Oncostatina M/genética , Fosforilación , Transducción de Señal , Proteínas Smad/genética , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoAsunto(s)
Bloqueo Atrioventricular/terapia , Estimulación Cardíaca Artificial , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Síndrome de Heterotaxia/complicaciones , Marcapaso Artificial , Vena Cava Superior/cirugía , Adulto , Bloqueo Atrioventricular/diagnóstico , Bloqueo Atrioventricular/etiología , Bloqueo Atrioventricular/fisiopatología , Síndrome de Heterotaxia/diagnóstico por imagen , Síndrome de Heterotaxia/cirugía , Humanos , Masculino , Resultado del Tratamiento , Vena Cava Superior/anomalías , Vena Cava Superior/diagnóstico por imagenAsunto(s)
Aterosclerosis , Enfermedad de la Arteria Coronaria , Adipoquinas , Humanos , Neurregulinas , Factores de RiesgoRESUMEN
BACKGROUND: The prevalence of pulmonary arterial hypertension (PAH) in primary Sjögren's syndrome (SS) had been reported to be rare. However, recent studies using echocardiography as a screening method showed conflicting results, and the true prevalence is still unclear. Since diagnosing primary SS is difficult because of its heterogeneous nature, a number of patients with primary-SS-associated PAH may be misdiagnosed with idiopathic PAH, losing their chance to undergo immunosuppressive therapy. Therefore, we sought to elucidate the prevalence of primary SS among patients who initially present with PAH. METHODS: From our prospective institutional PAH database, 40 consecutive patients without any obvious cause of PAH at the time of PAH diagnosis were identified. We retrospectively evaluated the prevalence of primary SS diagnosed during or after the initial assessment of PAH. RESULTS: During the initial assessment, one patient was diagnosed with primary-SS-associated PAH. Among the 25 patients who were initially diagnosed with idiopathic PAH, five were diagnosed with primary SS during their course of the disease. Of the five patients, three had key signs suggesting primary SS and were probably underdiagnosed at the time of initial evaluation. The remaining two patients, who were finally diagnosed with primary SS, did not have any specific signs suggesting primary SS at the time of initial evaluation but showed positive conversion of their autoantibodies during the course of PAH. CONCLUSION: The prevalence of primary-SS-associated PAH may be relatively high among patients who undergo initial evaluation for PAH. Furthermore, primary-SS-associated PAH may be underdiagnosed with routine evaluation for the primary cause of PAH. Clinicians should pay specific attention and carefully evaluate the possibility of primary SS in patients with PAH.
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Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/epidemiología , Adulto , Femenino , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Prospectivos , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/terapia , Adulto JovenRESUMEN
Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related complication characterized by severe progressive pulmonary hypertension. Antemortem diagnosis is difficult owing to the rapid progression of the condition, especially when the patient has no known malignancies and initially presents with pulmonary hypertension. Here we report a case of PTTM due to occult gastric cancer with metastasis in the left supraclavicular lymph node, also known as Virchow's node. Enlarged Virchow's node is an important indicator of advanced gastric cancer. In patients with progressive pulmonary hypertension of unknown origin, enlarged Virchow's node can be an important indicator for the diagnosis of PTTM.