Galectin-1, a novel promising target for outcome prediction and treatment in SCLC.

INTRODUCTION: small-cell lung cancer (SCLC) is one of the most lethal malignancies. Its management is complex due to the lack of biomarkers and limited therapies. Galectin-1 (Gal-1) plays a major role in cancer development and progression. The aim of this study is to assess whether Gal-1 has a predictive role in the disease evolution and its therapeutic potential. MATERIAL AND METHODS: The expression level of Gal-1 was examined by using a public RNA-sequencing (77 SCLC patients) and in-house immunohistochemistry (IHC) performed on biopsies from 81 patients. Survival curves and Cox regression analysis were used to assess the prognostic potential of Gal-1. In addition, a SCLC-PDX model was carried out and treated with either OTX008, an inhibitor of Gal-1, or vehicle to assess the effects of Gal-1 inhibition on this disease in vivo. RESULTS: Galectin-1 gene (LGALS1) expression showed a strong negative correlation with outcome in SCLC patients with advanced disease (p = 0.007). IHC unveiled that overall survival (OS) was significantly lower among extensive-stage SCLC (ES-SCLC) patient group with increased level of Gal-1 and platelet-to-lymphocyte ratio (PLR) (HR=3.07, 95% CI: 1.62, 5.79, p < 0.001). The SCLC-PDX model showed a significant reduction in tumor size (tumor growth inhibition [TGI] index 73%) without side effects. DISCUSSION: in this study, high levels of Gal-1 and PLR were associated with poorer OS in SCLC patients, supporting their utility as clinical prognostic biomarkers. Moreover, the in vivo model suggests the inhibition of Gal-1 as a novel potential therapy for this disease with very poor prognosis.

Vitamin C activates pyruvate dehydrogenase (PDH) targeting the mitochondrial tricarboxylic acid (TCA) cycle in hypoxic KRAS mutant colon cancer.

Background: In hypoxic tumors, positive feedback between oncogenic KRAS and HIF-1α involves impressive metabolic changes correlating with drug resistance and poor prognosis in colorectal cancer. Up to date, designed KRAS-targeting molecules do not show clear benefits in patient overall survival (POS) so pharmacological modulation of aberrant tricarboxylic acid (TCA) cycle in hypoxic cancer has been proposed as a metabolic vulnerability of KRAS-driven tumors. Methods: Annexin V-FITC and cell viability assays were carried out in order to verify vitamin C citotoxicity in KRAS mutant SW480 and DLD1 as well as in Immortalized Human Colonic Epithelial Cells (HCEC). HIF1a expression and activity were determined by western blot and functional analysis assays. HIF1a direct targets GLUT1 and PDK1 expression was checked using western blot and qRT-PCR. Inmunohistochemical assays were perfomed in tumors derived from murine xenografts in order to validate previous observations in vivo. Vitamin C dependent PDH expression and activity modulation were detected by western blot and colorimetric activity assays. Acetyl-Coa levels and citrate synthase activity were assessed using colorimetric/fluorometric activity assays. Mitochondrial membrane potential (Δψ) and cell ATP levels were assayed using fluorometric and luminescent test. Results: PDK-1 in KRAS mutant CRC cells and murine xenografts was downregulated using pharmacological doses of vitamin C through the proline hydroxylation (Pro402) of the Hypoxia inducible factor-1(HIF-1)α, correlating with decreased expression of the glucose transporter 1 (GLUT-1) in both models. Vitamin C induced remarkable ATP depletion, rapid mitochondrial Δψ dissipation and diminished pyruvate dehydrogenase E1-α phosphorylation at Serine 293, then boosting PDH and citrate synthase activity. Conclusion: We report a striking and previously non reported role of vitamin C in the regulation of the pyruvate dehydrogenase (PDH) activity, then modulating the TCA cycle and mitochondrial metabolism in KRAS mutant colon cancer. Potential impact of vitamin C in the clinical management of anti-EGFR chemoresistant colorectal neoplasias should be further considered.

Papel de la inflamación en la etiopatogenia de la EPOC / Role of inflammation in the etiopathogenesis of COPD

La inflamación es una de las primeras respuestas que presenta el sistema inmunitario del organismo parahacer frente a cualquier tipo de agresión. La lesión que produce la inhalación del humo del tabaco desarrollauna respuesta inflamatoria que inicialmente se desencadena de manera innata, como sucede en cualquiertipo de agresión. Posteriormente se ve estimulada por la liberación de diferentes factores químicos que potencianla respuesta inflamatoria y, finalmente, dependiendo del tipo de agresión, llega a activar la inmunidadadquirida que, mediada por la participación de los linfocitos, sirve para establecer una barrera física contra lapropagación de la lesión y para promover la recuperación del tejido pulmonar dañado. Sin embargo, el equilibrioentre inflamación y reparación no siempre se mantiene, como sucede en el caso de la enfermedad pulmonarobstructiva crónica (EPOC), donde aparecen marcados cambios en la arquitectura de las vías aéreas,espacios alveolares y arterias pulmonares, que suponen el trasfondo estructural de los cambios funcionalescaracterísticos de esta enfermedad.Siendo la EPOC una enfermedad básicamente pulmonar, disponemos de datos acerca de la existencia de unainflamación asociada a nivel sistémico. Los orígenes de esta inflamación sistémica no están aclarados, hayinformación acerca de un origen común directo del humo del tabaco a todos los niveles y datos acerca de unainflamación primaria pulmonar que, por extensión, afecta secundariamente a nivel sistémico. En la presenterevisión se describen los principales mecanismos implicados en el proceso inflamatorio existente a nivelpulmonar y a nivel sistémico en la EPOC(AU)

Inflammation is one of the first immune system responses to any type of aggression. As with any type ofaggression, the lesion produced by inhalation of tobacco smoke prompts an innate inflammatory response.Subsequently, this lesion is stimulated by the release of various chemical factors that enhance theinflammatory response and, finally — depending on the type of aggression — acquired immunity is activated,which, mediated by lymphocyte participation, serves to establish a physical barrier against the propagationof the lesion and to aid repair of the damaged pulmonary tissue. However, the balance between inflammationand repair is not always maintained, as is the case in chronic obstructive pulmonary disease (COPD), in whichmarked changes appear in the architecture of the airways, alveolar spaces and pulmonary arteries, formingthe structural background of the functional changes characteristic of this disease.COPD is basically a pulmonary disease but data are available on the existence of associated systemicinflammation. The origins of this systemic inflammation are unclear: some information indicates that tobaccosmoke is a direct origin common to local and systemic inflammation, while other data point to primarypulmonary inflammation that secondarily produces systemic involvement. The present review describes themain mechanisms involved in both pulmonary and systemic inflammation in COPD(AU)

El factor de crecimiento de hígado mejora la fibrosis pulmonar inducida tras la administración de cadmio en ratas / Liver growth factor improves pulmonary fibrosis secondary to cadmium administration in mice

IntroducciónEl liver growth factor (LGF, ‘factor de crecimiento de hígado’) es un mitógeno con actividad regeneradora y antifibrótica con actividad incluso en localizaciones extrahepáticas. En este trabajo se administró LGF en un modelo de fibrosis pulmonar inducido con cloruro de cadmio (CdCl2) para estudiar su capacidad antifibrótica.MétodosSe instilaron 42 ratas Wistar macho con 0,5ml/rata de CdCl2 al 0,025% (n=21) o de salino (n=21). Transcurridos 35 días y una vez establecida la lesión se realizó el tratamiento con LGF y posteriormente el análisis de los parámetros funcionales —capacidad inspiratoria (CI), complianza pulmonar (CL), capacidad vital forzada (CVF) y flujo espiratorio forzado al 75% (FEF75%)—, morfometría —área interna alveolar y distancia media entre paredes alveolares— y contenido en colágeno y elastina.ResultadosLa fibrosis pulmonar originada mediante CdCl2 se caracterizó por un marcado descenso de la función pulmonar en comparación con los controles. Se redujó un 28% la CI, un 38% la CL, un 31% la CVF y un 54% la FEF75%, descenso que se revirtió parcialmente tras la inyección de LGF —el 18% en CI, el 27% en CL, el 19% en CVF y el 35% en FEF75&%#x02014;. Además, se observó un incremento en la cantidad de colágeno y elastina del 165 y el 76%, respectivamente, en las ratas del grupo CdCl2 frente a un 110 y un 34% tras la inyección de LGF.ConclusionesEstos datos demuestran que el LGF mejora la función pulmonar y revierte parcialmente el incremento de las proteínas de matriz pulmonar producido por la instilación con CdCl2(AU)

IntroductionLiver growth factor (LGF) is a liver mitogen with regenerating and anti-fibrotic activity even at extrahepatic sites. We used LGF in a lung fibrosis model induced by cadmium chloride (CdCl2), to study its antifibrotic capacity.MethodsForty-two male Wistar rats were administered a single dose of 0.5ml/rat of CdCl2 0.025% (n=21) or the same volume of saline (control group, n=21). After 35 days, once a lesion was established, we started a 3 week treatment with LGF, after which we determined lung function —inspiratory capacity (IC), lung compliance (LC), forced vital capacity (FVC) and expiratory flow at 75% (FEF75%)—, lung morphometry —alveolar internal area (AIA), mean linear intersection (LM)—, and collagen (both by Sirius red and hydroxyproline residues) and elastin contents.ResultsPulmonary fibrosis in CdCl2 rats was characterized by a marked decrease in pulmonary function with respect to healthy controls —reductions of 28% in IC, 38% in CL, 31% in FVC, and 54% in FEF75&%#x02014; which was partially recovered after LGF injection —18% IC, 27% CL, 19% FVC and 35% FEF75&%#x02014;; increase in collagen and elastin contents —165% and 76%, respectively, in CdCl2 rats, versus 110% and 34% after LGF injection—; and increases in AIA and LM, partially reverted by LGF. Conclusions: Together, these data seem to demonstrate that LGF is able to improve lung function and partially reverts the increase in lung matrix proteins produced by CdCl2 instillation(AU)