RESUMEN
BACKGROUND AND AIMS: The role of inflammation in type 2 diabetes mellitus (T2D) remains unclear. We investigated the associations of high sensitivity C-reactive protein (hsCRP) concentration with T2D and glycemic traits using two-sample Mendelian Randomization. METHODS AND RESULTS: We used publically available summary-statistics data from genome-wide association studies on T2D (DIAGRAM: 12 171 cases; 56 862 controls) and glycemic traits (MAGIC: 46 186 participants without diabetes mellitus). We combined the effects of the genetic instrumental variables through inverse-variance weighting (IVW), and MR-Egger regression and weighted-median estimation as sensitivity analyses which take into account potential violations (e.g., directional pleiotropy) of the assumptions of instrumental variable analyses. Analyses were conducted using 15 known hsCRP genetic instruments among which 6 instruments are hsCRP specific and not involved in inflammatory processes beyond hsCRP concentration regulation. Though we found no association between the combined effect of the genetic instrumental variables for hsCRP and T2D with IVW (odds ratio per 1 ln [hsCRP in mg/L]: 1.15; 95% confidence interval: 0.93, 1.42), we found associations for T2D with MR-Egger regression and weighted-median estimation (odds ratio with 95% confidence interval per 1 ln [hsCRP in mg/L], MR-Egger regression: 1.29; 1.08, 1.49; weighted-median estimator: 1.21; 1.02, 1.39). We found no association with T2D for the combination of hsCRP-specific genetic instruments nor did we found associations with glycemic traits in any of the analyses. CONCLUSION: Evidence was provided for a potential causal association between hsCRP and T2D, but only after considering directional pleiotropy. However, hsCRP was not causally associated with glycemic traits.
Asunto(s)
Glucemia/genética , Proteína C-Reactiva/genética , Diabetes Mellitus Tipo 2/genética , Inflamación/genética , Biomarcadores/sangre , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/diagnóstico , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/sangre , Inflamación/diagnóstico , Mediadores de Inflamación/sangre , Resistencia a la Insulina/genética , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Factores de RiesgoAsunto(s)
Aminoácidos/sangre , Diabetes Mellitus Tipo 2/sangre , Biomarcadores/sangre , Glucemia/metabolismo , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Estudios de Asociación Genética , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Polimorfismo de Nucleótido Simple , Medición de Riesgo , Factores de Riesgo , Regulación hacia ArribaRESUMEN
Endoglin, a transforming growth factor-ß co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.