SUMMARY The neuropsychological performances, outcome of epilepsy and MRI topography of tubers of 23 children with tuberous sclerosis were reviewed. Seven children had normal intelligence, 10 had mental retardation, and six mental retardation and autism. An adverse association was found between the number of lesions and IQ, behaviour and severity of epilepsy. Posterior lesions, in addition to frontal‐lobe dysfunction, were observed in children with autism. Tuberous sclerosis with well‐defined cerebral lesions may represent a model for the relationship between different neuropsychiatric problems. RÉSUMÉ Aspects neuropsychologiques de la sclérose tubéreuse: relations avec l'épilepsie et les données IRM Les performances neuropsychologiques, le devenir de l'épilepsie et la topographie IRM des tubers chez 23 enfants présentant une sclérose tubéreuse ont été déterminés. Sept enfants avaient une intelligence normale, dix avaient un retard mental, et six un retard mental avec autisme. Une correlation inverse a été trouvée entre le nombre de lésions et le QI, le comportement et la gravité de l'épilepsie. Des lésions postérieures, associées à une dysfonctionnement du lobe frontal, ont été observées chez les enfants avec autisme. La sclérose tubéreuse avec lésions cérébrales bien définies peut représenter un modèle de la relation existant entre les différents problèmes neuropsychiatriques. ZUSAMMENFASSUNG Neurophysiologische Aspekte der tuberösen Hirnsklerose: Relation zu Epilepsie und MRI Befunden Bei 23 Kinder mit tuberöser Hirnsklerose wurden die neurophysiologischen Leistungen, der Epilepsiebefund und die Topographie der tuberösen Veränderungen im MRI untersucht. Sieben Kinder hatten eine normale Intelligenz, 10 eine geistige Retardierung und sechs eine geistigen Retardierung mit Autismus. Es fand sich eine negative Beziehung zwischen der Anzahl der Läsionen und dem IQ, dem Verhalten und dem Schweregrad der Epilepsie. Bei Kindern mit Autismus wurden posteriore Läsionen in Verbindung mit Dysfunktionen im Frontallappen beobachtet. Die tuberöse Sklerose mit genau definierten Hirnläsionen kann als Modell dienen für Beziehungen zwischen Morphologie und verschiedenen neuropsychiatrischen Störungen. RESUMEN Aspectos neuropsicológicos de la esclerosis tuberosa en relación con la epilepsia y los hallazgos de la IRM Se revisaron las características neuropsicológicas, el curso de la epilepsia y la topografía de los tuberomas en la IRM en 23 niños con esclerosis tuberosa. Siete niños tenian una intelligencia normal, 10 tenian un retraso mental y seis retraso mental y autismo. Se halló una asociacion adversa entre el número de lesiones y el CI, el comportamiento y la gravedad de la epilepsia. En niños con autismo se observaron lesiones posteriores, además de la disfunción del lóbulo frontal La esclerosis tuberosa con lesiones cerebrales bien definidas puede representar un modelo de las relaciones entre diferentes problemas neuropsiquiátricos.

Transforming growth factor-β (TGF-β) is a pleiotropic growth factor with broad tissue distribution that plays critical roles during embryonic development, normal tissue homeostasis, and cancer. While its cytostatic activity on normal epithelial cells initially defined TGF-β signaling as a tumor suppressor pathway, there is ample evidence indicating that TGF-β is a potent pro-tumorigenic agent, acting via autocrine and paracrine mechanisms to promote peri-tumoral angiogenesis, together with tumor cell migration, immune escape, and dissemination to metastatic sites. This review summarizes the current knowledge on the implication of TGF-β signaling in melanoma.

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A close association between pericytes and endothelial cells (ECs) is crucial to the stability and function of capillary blood vessels and microvessels. The loss or dysfunction of pericytes results in significant disruption of these blood vessels as observed in pathological conditions, including cancer, diabetes, stroke, and Alzheimer’s disease. Prostaglandin E2 (PGE2) is a lipid mediator of inflammation, and its tissue concentration is elevated in cancer and neurological disorders. Here, we show that the exposure to PGE2 switches pericytes to a fast-migrating, loosely adhered phenotype that fails to intimately interact with ECs. N-cadherin and connexin-43 in adherens junction and gap junction between pericytes and ECs are downregulated by EP-4 and EP-1-dependent mechanisms, leading to breakdown of the pericyte–EC interaction. Furthermore, R-Ras, a small GTPase important for vascular normalization and vessel stability, is transcriptionally repressed by PGE2 in an EP4-dependent manner. Mouse dermal capillary vessels lose pericyte coverage substantially upon PGE2 injection into the skin. Our results suggest that EP-mediated direct disruption of pericytes by PGE2 is a key process for vascular destabilization. Restoring pericyte–EC interaction using inhibitors of PGE2 signaling may offer a therapeutic strategy in cancer and neurological disorders, in which pericyte dysfunction contributes to the disease progression.

In melanoma cells, high expression of the transcription factor GLI2 is associated with increased invasive potential and loss of E-cadherin expression, an event reminiscent of the epithelial-to-mesenchymal transition (EMT). Herein, we provide evidence that GLI2 represses E-cadherin gene (CDH1) expression in melanoma cells via distinct mechanisms, enhancing transcription of the EMT-activator ZEB1 and cooperative repression of CDH1 gene transcription via direct binding of both GLI2 and ZEB1 to two closely positioned Kruppel-like factor-binding sites within the CDH1 promoter. GLI2 silencing rescued CDH1 expression except in melanoma cell lines in which the CDH1 promoter was hypermethylated. Proximity ligation assays identified GLI2-ZEB1 complexes in melanoma cell nuclei, proportional to endogenous GLI2 and ZEB1 expression, and whose accumulation was enhanced by the classical EMT inducer TGF-β. These data identify GLI2 as a critical modulator of the cadherin switch in melanoma, a molecular process that is critical for metastatic spread of the disease.

The increase in cAMP levels in endothelial cells triggers cellular signaling to alter vascular permeability. It is generally considered that cAMP signaling stabilizes the endothelial barrier function and reduces permeability. However, previous studies have only examined the permeability shortly after cAMP elevation and thus have only investigated acute responses. Because cAMP is a key regulator of gene expression, elevated cAMP may have a delayed but profound impact on the endothelial permeability by altering the expression of the genes that are vital for the vessel wall stability. The small guanosine triphosphate hydrolase Ras-related protein (R-Ras) stabilizes VE-cadherin clustering and enhances endothelial barrier function, thereby stabilizing the integrity of blood vessel wall. Here we show that cAMP controls endothelial permeability through RRAS gene regulation. The prolonged cAMP elevation transcriptionally repressed RRAS in endothelial cells via a cAMP response element–binding 3 (CREB3)–dependent mechanism and significantly disrupted the adherens junction. These effects resulted in a marked increase of endothelial permeability that was reversed by R-Ras transduction. Furthermore, cAMP elevation in the endothelium by prostaglandin E2 or phosphodiesterase type 4 inhibition caused plasma leakage from intact microvessels in mouse skin. Our study demonstrated that, contrary to the widely accepted notion, cAMP elevation in endothelial cells ultimately increases vascular permeability, and the cAMP-dependent RRAS repression critically contributes to this effect.—Perrot, C. Y., Sawada, J., Komatsu, M. Prolonged activation of cAMP signaling leads to endothelial barrier disruption via transcriptional repression of RRAS.

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