RESUMEN
Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I , Malformaciones Vasculares , Humanos , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Animales , Malformaciones Vasculares/genética , Malformaciones Vasculares/patología , Malformaciones Vasculares/fisiopatología , Malformaciones Vasculares/metabolismo , Malformaciones Vasculares/enzimología , Células Endoteliales/enzimología , Células Endoteliales/patología , Células Endoteliales/metabolismo , Estrés Mecánico , Mutación con Ganancia de Función , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Transducción de Señal , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/fisiopatología , Hemangioma Cavernoso del Sistema Nervioso Central/patologíaRESUMEN
Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies characterized by aberrant and enlarged lymphatic and blood vessels. CLVM appear during fetal development and enlarge after birth, causing life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and disfigurement. Treatment includes surgical debulking, amputation, and recurrent sclerotherapy. Somatic, mosaic mutations in the 110-kD catalytic α-subunit of phosphoinositide-3-kinase (PIK3CA) gene have been previously identified in affected tissues from CLVM patients; however, the cell population harboring the mutation is still unknown. In this study, we hypothesized that endothelial cells (EC) carry the PIK3CA mutations and play a major role in the cellular origin of CLVM. We isolated EC from the lesions of seven patients with CLVM and identified PIK3CA hotspot mutations. The CLVM EC exhibited constitutive phosphorylation of the PI3K effector AKT as well as hyperproliferation and increased resistance to cell death compared to normal EC. Inhibitors of PIK3CA (BYL719) and AKT (ARQ092) attenuated the proliferation of CLVM EC in a dose-dependent manner. A xenograft model of CLVM was developed by injecting patient-derived EC into the flanks of immunocompromised mice. CLVM EC formed lesions with enlarged lymphatic and vascular channels, recapitulating the patient histology. EC subpopulations were further obtained by both immunomagnetic separation into lymphatic EC (LEC) and vascular EC (VEC) and generation of clonal populations. By sequencing these subpopulations, we determined that both LEC and VEC from the same patient express the PIK3CA mutation, exhibit increased AKT activation and can form lymphatic or vascular lesions in mouse.
Asunto(s)
Capilares/anomalías , Fosfatidilinositol 3-Quinasa Clase I , Células Endoteliales de la Vena Umbilical Humana , Vasos Linfáticos , Mutación , Malformaciones Vasculares , Adulto , Animales , Capilares/enzimología , Capilares/patología , Preescolar , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Femenino , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Lactante , Vasos Linfáticos/anomalías , Vasos Linfáticos/enzimología , Vasos Linfáticos/patología , Masculino , Ratones , Ratones Desnudos , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Malformaciones Vasculares/patologíaRESUMEN
Vascular anomalies (VAs) may be associated with significant morbidity and mortality. The aim of this study was to evaluate the efficacy and safety of sirolimus (rapamycin) in the treatment of children and young adults with complicated VAs. A retrospective chart was created that included 19 patients treated with sirolimus for complicated VAs. Concurrently, a search of the PubMed database for VA cases treated with sirolimus was conducted. Descriptive analysis was performed and the efficiency rate of sirolimus was calculated. This retrospective study included 19 patients, 17 of whom were treated with oral sirolimus and 2 with topical sirolimus. Clinical improvement occurred in 15 patients (79%). One patient experienced near-complete resolution. Only 2 patients showed poor response and discontinued treatment. The literature review analysed 150 cases of VA treated with sirolimus. Sirolimus was efficient in 85% of cases, including 5 cases of complete resolution. Sirolimus appears to be an effective and safe treatment for children and young adults with complicated VAs.
Asunto(s)
Antineoplásicos/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Sirolimus/administración & dosificación , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Malformaciones Vasculares/tratamiento farmacológico , Neoplasias Vasculares/tratamiento farmacológico , Administración Cutánea , Administración Oral , Adolescente , Factores de Edad , Antineoplásicos/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Israel , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Inducción de Remisión , Estudios Retrospectivos , Transducción de Señal , Sirolimus/efectos adversos , Serina-Treonina Quinasas TOR/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/enzimología , Neoplasias Vasculares/diagnóstico , Neoplasias Vasculares/enzimología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Recently, it has been discovered that a subset of vascular malformations, of the lymphatic and venous type, are caused by oncogenic mutations in the PIK3CA gene. Now, efforts have been focused in the understanding of the molecular and cellular consequences of these mutations and the opportunities for novel-targeted therapies for these diseases. RECENT FINDINGS: Here, we review the latest findings in the biology of oncogenic PIK3CA mutations in the pathogenesis of vascular malformations. We focus on the recent development of in-vitro and in-vivo tools for the study of PIK3CA-mutant vascular malformations with special interest in preclinical models for drug testing. Also, we review the latest advances in phosphoinositide 3-kinase (PI3K) inhibitors in the clinic and their repurposing for the treatment of lymphatic malformations and venous malformations. SUMMARY: Oncogenic mutations on PIK3CA causing lymphatic malformations and venous malformations are also frequently found in epithelial cancer. Thus, fundamental research done in the cancer field during the past decades might be applied to the understanding of lymphatic malformations and venous malformations. Likewise, repurposing PI3K pathway inhibitors that are currently in cancer clinical trials can be used as a novel strategy for the treatment of these diseases. Here, we also open a debate for the consideration of lymphatic malformations and venous malformations as developmental tumours.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I , Inhibidores Enzimáticos/uso terapéutico , Mutación , Transducción de Señal , Malformaciones Vasculares , Animales , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Humanos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Glandulares y Epiteliales/tratamiento farmacológico , Neoplasias Glandulares y Epiteliales/epidemiología , Neoplasias Glandulares y Epiteliales/genética , Neoplasias Glandulares y Epiteliales/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Malformaciones Vasculares/patologíaRESUMEN
PURPOSE OF REVIEW: Capillary malformations, the most common type of vascular malformation, are caused by a somatic mosaic mutation in GNAQ, which encodes the Gαq subunit of heterotrimeric G-proteins. How the single amino acid change - predicted to activate Gαq - causes capillary malformations is not known but recent advances are helping to unravel the mechanisms. RECENT FINDINGS: The GNAQ R183Q mutation is present not only in endothelial cells isolated from skin and brain capillary malformations but also in brain tissue underlying the capillary malformation, raising questions about the origin of capillary malformation-causing cells. Insights from computational analyses shed light on the mechanisms of constitutive activation and new basic science shows Gαq plays roles in sensing shear stress and in regulating cerebral blood flow. SUMMARY: Several studies confirm the GNAQ R183Q mutation in 90% of nonsyndromic and Sturge-Weber syndrome (SWS) capillary malformations. The mutation is enriched in endothelial cells and blood vessels isolated from skin, brain, and choroidal capillary malformations, but whether the mutation resides in other cell types must be determined. Further, the mechanisms by which the R183Q mutation alters microvascular architecture and blood flow must be uncovered to develop new treatment strategies for SWS in particular, a devastating disease for which there is no cure.
Asunto(s)
Capilares , Subunidades alfa de la Proteína de Unión al GTP Gq-G11 , Mutación Missense , Proteínas de Neoplasias , Síndrome de Sturge-Weber , Malformaciones Vasculares , Sustitución de Aminoácidos , Animales , Capilares/enzimología , Capilares/patología , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Humanos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Síndrome de Sturge-Weber/enzimología , Síndrome de Sturge-Weber/genética , Síndrome de Sturge-Weber/patología , Síndrome de Sturge-Weber/terapia , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Malformaciones Vasculares/patología , Malformaciones Vasculares/terapiaRESUMEN
Vascular anomalies are typically classified into two major categories, vascular tumors and vascular malformations. Most vascular malformations are caused sporadically by somatic mosaic gene mutations, and genetic analyses have advanced our understanding of the biomolecular mechanisms involved in their pathogenesis. Culprit gene mutations typically involve two major signaling pathways; the RAS/MAPK/ERK pathway is typically involved in fast-flow arteriovenous malformations, whereas the PI3K/AKT/mTOR pathway is typically mutated in slow-flow venous and lymphatic malformations. These findings suggest new therapeutic approaches to vascular malformations, focusing on targeting the etiologic mutated pathways. This review summarizes the currently available literature reflecting the updated International Society for Study of Vascular Anomalies classification system with emphasis on potential therapeutic targets that will provide vascular surgeons with an updated perspective on the etiologic basis of vascular malformations, allowing improved multidisciplinary collaboration.
Asunto(s)
Mutación , Transducción de Señal/genética , Malformaciones Vasculares/genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Pronóstico , Factores de Riesgo , Malformaciones Vasculares/diagnóstico por imagen , Malformaciones Vasculares/enzimologíaRESUMEN
CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Lipoma/tratamiento farmacológico , Lipoma/enzimología , Terapia Molecular Dirigida , Anomalías Musculoesqueléticas/tratamiento farmacológico , Anomalías Musculoesqueléticas/enzimología , Nevo/tratamiento farmacológico , Nevo/enzimología , Tiazoles/uso terapéutico , Malformaciones Vasculares/tratamiento farmacológico , Malformaciones Vasculares/enzimología , Adulto , Animales , Niño , Modelos Animales de Enfermedad , Femenino , Células HeLa , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Ratones , Fenotipo , Escoliosis/complicaciones , Escoliosis/tratamiento farmacológico , Sirolimus/uso terapéutico , Síndrome , Neoplasias Vasculares/complicaciones , Neoplasias Vasculares/tratamiento farmacológicoRESUMEN
Giant congenital melanocytic nevi may be symptomatically isolated or syndromic. Associations with capillary malformations are exceptional, and development of epidermal cysts has not been described. A 71-year-old patient with a giant congenital melanocytic nevus (CMN) of the lower back, buttocks, and thighs was asymptomatic except for unexpected hemorrhage during partial surgical excision years before. Blunt trauma at age 64 initiated recurrent, severe pain under the nevus; multiple large epidermal cysts then developed within it. Imaging and biopsy showed a large, non-pulsatile venous malformation intermingled with the deep nevus. A low-abundance, heterozygous BRAF c.1799T>A (p.V600E) mutation was present in both gluteal and occipital congenital nevi; additional mutations in NRAS, GNAQ, GNA11, HRAS, or PIK3CA were undetectable. This is the first demonstration of a recurrent BRAF mutation in multiple large congenital nevi from the same individual, confirming that this malformation can have multiple genetic origins. Early constitutive activation of BRAF can therefore cause unusual associations of giant nevi with vascular malformations, indicating that both pigment and endothelial cell physiology may be affected by mosaic RASopathies.
Asunto(s)
Quiste Epidérmico , Mutación , Nevo Pigmentado , Proteínas Proto-Oncogénicas B-raf/genética , Malformaciones Vasculares , Anciano , Quiste Epidérmico/congénito , Quiste Epidérmico/enzimología , Quiste Epidérmico/patología , Quiste Epidérmico/cirugía , Humanos , Masculino , Nevo Pigmentado/congénito , Nevo Pigmentado/enzimología , Nevo Pigmentado/cirugía , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Malformaciones Vasculares/patologíaRESUMEN
Activin receptor-like kinase 1 (ALK1) is an endothelial serine-threonine kinase receptor for bone morphogenetic proteins (BMPs) 9 and 10. Inactivating mutations in the ALK1 gene cause hereditary haemorrhagic telangiectasia type 2 (HHT2), a disabling disease characterized by excessive angiogenesis with arteriovenous malformations (AVMs). Here we show that inducible, endothelial-specific homozygous Alk1 inactivation and BMP9/10 ligand blockade both lead to AVM formation in postnatal retinal vessels and internal organs including the gastrointestinal (GI) tract in mice. VEGF and PI3K/AKT signalling are increased on Alk1 deletion and BMP9/10 ligand blockade. Genetic deletion of the signal-transducing Vegfr2 receptor prevents excessive angiogenesis but does not fully revert AVM formation. In contrast, pharmacological PI3K inhibition efficiently prevents AVM formation and reverts established AVMs. Thus, Alk1 deletion leads to increased endothelial PI3K pathway activation that may be a novel target for the treatment of vascular lesions in HHT2.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Telangiectasia Hemorrágica Hereditaria/complicaciones , Malformaciones Vasculares/complicaciones , Malformaciones Vasculares/enzimología , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo II , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Modelos Animales de Enfermedad , Eliminación de Gen , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Ratones , Modelos Biológicos , Neovascularización Patológica/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Retina/patología , Transducción de Señal/efectos de los fármacos , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Vascular anomalies are broadly divided into vascular tumours and malformations. These lesions are composed of abnormal vascular elements of various types, and mainly affect infants, children, and young adults. Vascular anomalies may be painful, may be complicated by bleeding, infection, or organ dysfunction, and can have secondary effects on other tissues. Current treatment strategies include surgical excision, pulsed laser, and sclerotherapy, which are invasive, with risks of recurrence. There are growing pharmacological options for these vascular anomalies, but, to date, no specific targeted therapies have been developed. Phosphoinositide 3-kinases (PI3Ks) constitute a family of lipid kinases that are involved in signal transduction and vesicular traffic, and that modulate important cellular processes such as proliferation, growth, and migration. Recent findings have indicated that the PI3K signalling pathway is important in the pathogenesis of vascular anomalies. This provides an opportunity to use PI3K inhibitors, which are in clinical trials for cancer treatment, for such lesions. Here, we provide an update on the classification of vascular anomalies, with their major features, and discuss the role of the PI3K signalling pathway in the pathogenesis of vascular anomalies, and their clinical implications and therapeutic opportunities. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Asunto(s)
Fosfatidilinositol 3-Quinasas/fisiología , Malformaciones Vasculares/enzimología , Neoplasias Vasculares/enzimología , Humanos , Terapia Molecular Dirigida/métodos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Transducción de Señal/fisiología , Malformaciones Vasculares/clasificación , Malformaciones Vasculares/patología , Malformaciones Vasculares/terapia , Neoplasias Vasculares/clasificación , Neoplasias Vasculares/patología , Neoplasias Vasculares/terapiaRESUMEN
Patients with extensive lymphatic malformations associated with tissue overgrowth syndromes (such as Klippel-Trenaunay syndrome and CLOVES) often pose a therapeutic challenge for physicians. In recent years, it has been suggested that oral sildenafil therapy might be used to treat congenital lymphatic malformations. However, this possible new therapy has not yet been used in patients with lymphatic malformations associated with tissue overgrowth syndromes. A 30-year-old man with extensive capillary-lymphatic malformations of the right leg and thorax, and a tissue overgrowth syndrome caused by a somatic mutation in the PIK3CA gene, was treated with oral sildenafil due to symptoms of pain, dyspnea, and functional impairment. Several weeks after the start of the treatment, the patient reported softening of the lymphatic malformation and a significant improvement of his symptoms and physical condition. So far, sildenafil is still considered a last resort in the treatment of complex treatment-resistant lymphatic malformations. With this case report, we demonstrate that sildenafil could also be an alternative treatment option for lymphatic malformations in patients with syndromes belonging to the PIK3CA-related overgrowth spectrum.
Asunto(s)
Capilares/efectos de los fármacos , Anomalías Linfáticas/tratamiento farmacológico , Mutación , Fosfatidilinositol 3-Quinasas/genética , Citrato de Sildenafil/administración & dosificación , Malformaciones Vasculares/tratamiento farmacológico , Administración Oral , Adulto , Capilares/anomalías , Capilares/enzimología , Fosfatidilinositol 3-Quinasa Clase I , Predisposición Genética a la Enfermedad , Humanos , Anomalías Linfáticas/diagnóstico , Anomalías Linfáticas/enzimología , Anomalías Linfáticas/genética , Masculino , Fenotipo , Síndrome , Resultado del Tratamiento , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genéticaRESUMEN
Venous malformations (VMs) are painful and deforming vascular lesions composed of dilated vascular channels, which are present from birth. Mutations in the TEK gene, encoding the tyrosine kinase receptor TIE2, are found in about half of sporadic (nonfamilial) VMs, and the causes of the remaining cases are unknown. Sclerotherapy, widely accepted as first-line treatment, is not fully efficient, and targeted therapy for this disease remains underexplored. We have generated a mouse model that faithfully mirrors human VM through mosaic expression of Pik3ca(H1047R), a constitutively active mutant of the p110α isoform of phosphatidylinositol 3-kinase (PI3K), in the embryonic mesoderm. Endothelial expression of Pik3ca(H1047R)resulted in endothelial cell (EC) hyperproliferation, reduction in pericyte coverage of blood vessels, and decreased expression of arteriovenous specification markers. PI3K pathway inhibition with rapamycin normalized EC hyperproliferation and pericyte coverage in postnatal retinas and stimulated VM regression in vivo. In line with the mouse data, we also report the presence of activating PIK3CA mutations in human VMs, mutually exclusive with TEK mutations. Our data demonstrate a causal relationship between activating Pik3ca mutations and the genesis of VMs, provide a genetic model that faithfully mirrors the normal etiology and development of this human disease, and establish the basis for the use of PI3K-targeted therapies in VMs.
Asunto(s)
Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Animales , Proliferación Celular/efectos de los fármacos , Fosfatidilinositol 3-Quinasa Clase I , Células Endoteliales/efectos de los fármacos , Células Endoteliales/patología , Humanos , Mesodermo/efectos de los fármacos , Mesodermo/embriología , Mesodermo/patología , Ratones Endogámicos C57BL , Mosaicismo/efectos de los fármacos , Pericitos/efectos de los fármacos , Pericitos/patología , Receptor TIE-2/metabolismo , Sirolimus/farmacologíaRESUMEN
Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyenet al, 2014; Uebelhoeret al, 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limayeet al, 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.
Asunto(s)
Mutación/genética , Fosfatidilinositol 3-Quinasas/genética , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/genética , Animales , Fosfatidilinositol 3-Quinasa Clase I , Embrión de Mamíferos/irrigación sanguínea , Embrión de Mamíferos/efectos de los fármacos , Embrión de Mamíferos/patología , Células Endoteliales/metabolismo , Integrasas/metabolismo , Ratones , Neovascularización Fisiológica/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Piel/irrigación sanguínea , Piel/patología , Médula Espinal/irrigación sanguínea , Médula Espinal/patología , Malformaciones Vasculares/tratamiento farmacológicoRESUMEN
An 18-year-old man underwent liver transplantation due to an Abernethy malformation associated with multiple hepatocellular nodules including one which was rapidly enlarging and was suspicious for malignant transformation. Analysis of the explanted liver showed a spectrum of multiple hepatocellular nodules ranging in appearance from focal nodular hyperplasia, hepatocellular adenoma and to a well-differentiated hepatocellular neoplasm borderline for hepatocellular carcinoma. Mutational analysis revealed wild-type ß-catenin expression in the background liver and some nodules, whilst different variants were present in other lesions irrespective of their morphological appearance. No telomerase reverse transcriptase (TERT) promoter mutation was identified. Abernethy malformations can lead to independent genetic events which can result in ß-catenin mutations associated with malignant transformation of hepatocellular nodules. When following up such patients, one must therefore have a high index of suspicion, particularly if radiological surveillance reveals a change in the nature of hepatic lesions.
Asunto(s)
Adenoma de Células Hepáticas/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Hiperplasia Nodular Focal/genética , Neoplasias Hepáticas/genética , Mutación , Neoplasias Primarias Múltiples/genética , Malformaciones Vasculares/genética , beta Catenina/genética , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/enzimología , Adenoma de Células Hepáticas/cirugía , Adolescente , Biomarcadores de Tumor/análisis , Biopsia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/enzimología , Carcinoma Hepatocelular/cirugía , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Análisis Mutacional de ADN , Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/enzimología , Hiperplasia Nodular Focal/cirugía , Predisposición Genética a la Enfermedad , Glutamato-Amoníaco Ligasa/análisis , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/cirugía , Trasplante de Hígado , Imagen por Resonancia Magnética , Masculino , Neoplasias Primarias Múltiples/diagnóstico , Neoplasias Primarias Múltiples/enzimología , Neoplasias Primarias Múltiples/cirugía , Fenotipo , Malformaciones Vasculares/diagnóstico , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/cirugíaRESUMEN
Mammalian target of rapamycin (mTOR) inhibitors are a promising new treatment in vascular anomalies, but no published randomized controlled trials are available. The aim of this systematic review of all reported cases was to assess the efficacy and safety of mTOR inhibitors in all vascular anomalies, except cancers, in children and adults. In November 2014 MEDLINE, CENTRAL, LILACS and EMBASE were searched for studies of mTOR inhibitors in any vascular condition, except for malignant lesions, in humans. Fourteen publications and 9 posters, with data on 25 and 59 patients, respectively, all < 18 years old were included. Of these patients, 35.7% (n = 30) had vascular tumours, and 64.3% (n = 54) had malformations. Sirolimus was the most frequent mTOR inhibitor used (98.8%, n = 83). It was efficient in all cases, at a median time of 2 weeks (95% confidence interval 1-10 weeks). Sirolimus was well tolerated, the main side-effect being mouth sores, which led to treatment withdrawal in one case. The dosage of sirolimus was heterogeneous, the most common being 1.6 mg/m2/day.
Asunto(s)
Antineoplásicos/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Malformaciones Vasculares/tratamiento farmacológico , Neoplasias Vasculares/tratamiento farmacológico , Adolescente , Antineoplásicos/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Resultado del Tratamiento , Malformaciones Vasculares/enzimología , Neoplasias Vasculares/enzimologíaRESUMEN
Somatic mutations in TEK, the gene encoding endothelial cell tyrosine kinase receptor TIE2, cause more than half of sporadically occurring unifocal venous malformations (VMs). Here, we report that somatic mutations in PIK3CA, the gene encoding the catalytic p110α subunit of PI3K, cause 54% (27 out of 50) of VMs with no detected TEK mutation. The hotspot mutations c.1624G>A, c.1633G>A, and c.3140A>G (p.Glu542Lys, p.Glu545Lys, and p.His1047Arg), frequent in PIK3CA-associated cancers, overgrowth syndromes, and lymphatic malformation (LM), account for >92% of individuals who carry mutations. Like VM-causative mutations in TEK, the PIK3CA mutations cause chronic activation of AKT, dysregulation of certain important angiogenic factors, and abnormal endothelial cell morphology when expressed in human umbilical vein endothelial cells (HUVECs). The p110α-specific inhibitor BYL719 restores all abnormal phenotypes tested, in PIK3CA- as well as TEK-mutant HUVECs, demonstrating that they operate via the same pathogenic pathways. Nevertheless, significant genotype-phenotype correlations in lesion localization and histology are observed between individuals with mutations in PIK3CA versus TEK, pointing to gene-specific effects.
Asunto(s)
Mutación , Neovascularización Patológica/genética , Fosfatidilinositol 3-Quinasas/genética , Malformaciones Vasculares/genética , Alelos , Fosfatidilinositol 3-Quinasa Clase I , Regulación de la Expresión Génica , Frecuencia de los Genes , Estudios de Asociación Genética , Secuenciación de Nucleótidos de Alto Rendimiento , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Neovascularización Patológica/enzimología , Neovascularización Patológica/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Receptor TIE-2/antagonistas & inhibidores , Receptor TIE-2/genética , Receptor TIE-2/metabolismo , Transducción de Señal , Tiazoles/farmacología , Transfección , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/patología , Venas/enzimología , Venas/patologíaRESUMEN
Venous malformations (VMs) are localized defects in vascular morphogenesis frequently caused by mutations in the gene for the endothelial tyrosine kinase receptor TIE2. Here, we report the analysis of a comprehensive collection of 22 TIE2 mutations identified in patients with VM, either as single amino acid substitutions or as double-mutations on the same allele. Using endothelial cell (EC) cultures, mouse models and ultrastructural analysis of tissue biopsies from patients, we demonstrate common as well as mutation-specific cellular and molecular features, on the basis of which mutations cluster into categories that correlate with data from genetic studies. Comparisons of double-mutants with their constituent single-mutant forms identified the pathogenic contributions of individual changes, and their compound effects. We find that defective receptor trafficking and subcellular localization of different TIE2 mutant forms occur via a variety of mechanisms, resulting in attenuated response to ligand. We also demonstrate, for the first time, that TIE2 mutations cause chronic activation of the MAPK pathway resulting in loss of normal EC monolayer due to extracellular matrix (ECM) fibronectin deficiency and leading to upregulation of plasminogen/plasmin proteolytic pathway. Corresponding EC and ECM irregularities are observed in affected tissues from mouse models and patients. Importantly, an imbalance between plasminogen activators versus inhibitors would also account for high d-dimer levels, a major feature of unknown cause that distinguishes VMs from other vascular anomalies.
Asunto(s)
Receptor TIE-2/genética , Malformaciones Vasculares/genética , Sustitución de Aminoácidos , Animales , Movimiento Celular/genética , Células Endoteliales/metabolismo , Femenino , Productos de Degradación de Fibrina-Fibrinógeno , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ligandos , Ratones , Ratones SCID , Mutación , Fosforilación , Receptor TIE-2/metabolismo , Transducción de Señal , Esferoides Celulares , Malformaciones Vasculares/enzimologíaRESUMEN
The detoxification of ammonia occurs mainly through conversion of ammonia to urea in the liver via the urea cycle and glutamine synthesis. Congenital portosystemic shunts (CPSS) in dogs cause hyperammonemia eventually leading to hepatic encephalopathy. In this study, the gene expression of urea cycle enzymes (carbamoylphosphate synthetase (CPS1), ornithine carbamoyltransferase (OTC), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase (ARG1)), N-acetylglutamate synthase (NAGS), Glutamate dehydrogenase (GLUD1), and glutamate-ammonia ligase (GLUL) was evaluated in dogs with CPSS before and after surgical closure of the shunt. Additionally, immunohistochemistry was performed on urea cycle enzymes and GLUL on liver samples of healthy dogs and dogs with CPSS to investigate a possible zonal distribution of these enzymes within the liver lobule and to investigate possible differences in distribution in dogs with CPSS compared to healthy dogs. Furthermore, the effect of increasing ammonia concentrations on the expression of the urea cycle enzymes was investigated in primary hepatocytes in vitro. Gene-expression of CPS1, OTC, ASL, GLUD1 and NAGS was down regulated in dogs with CPSS and did not normalize after surgical closure of the shunt. In all dogs GLUL distribution was localized pericentrally. CPS1, OTC and ASS1 were localized periportally in healthy dogs, whereas in CPSS dogs, these enzymes lacked a clear zonal distribution. In primary hepatocytes higher ammonia concentrations induced mRNA levels of CPS1. We hypothesize that the reduction in expression of urea cycle enzymes, NAGS and GLUD1 as well as the alterations in zonal distribution in dogs with CPSS may be caused by a developmental arrest of these enzymes during the embryonic or early postnatal phase.
Asunto(s)
Amoníaco/metabolismo , Redes y Vías Metabólicas , Vena Porta/anomalías , Urea/metabolismo , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/veterinaria , Amoníaco/farmacología , Cloruro de Amonio/farmacología , Animales , Células Cultivadas , Perros , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato-Amoníaco Ligasa/metabolismo , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Inmunohistoquímica , Hígado/efectos de los fármacos , Hígado/enzimología , Análisis de Secuencia por Matrices de Oligonucleótidos , Vena Porta/enzimología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal/genética , Malformaciones Vasculares/genéticaRESUMEN
Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.