Angiogenesis and pancreatic cancer: a role for tissue plasminogen activator (tPA)
Loading...
Document Type
Document Version
Author
Director
Navarro Medrano, Pilar
Tutor
Other authors
Publication Date
Pages
156 p.
Embargo date
Citation
Mohan, R. Angiogenesis and pancreatic cancer: a role for tissue plasminogen activator (tPA). Universitat Pompeu Fabra; 2011. handle: http://hdl.handle.net/10803/38526
This citation was generated automatically.
Citation
Doctoral program
Programa de doctorat en Biomedicina
Abstract
El adenocarcinoma ductal pancreático (PDAC) es la quinta causa de muerte por cáncer en los países desarrollados y uno de los tumores humanos más agresivos. A pesar del papel clave de la angiogénesis -la formación de nuevos vasos a partir de otros preexistentes- en la progresión y metástasis de muchos tumores, su papel en PDAC ha sido poco caracterizado. El activador tisular del plasminógeno (tPA), una proteína multifuncional que regula numerosas funciones celulares, ejerce efectos proangiogénicos en modelos in vivo de PDAC, aunque no se han analizado los mecanismos moleculares responsables de estos efectos. Esta tesis trata de identificar el papel de tPA en la angiogénesis del PDAC, así como de descubrir los factores responsables de la sobreexpresión de tPA en cáncer de páncreas. En primer lugar, hemos demostrado que los efectos pro-angiogénicos de tPA pueden ser tanto directos como indirectos. Por un lado, aunque tPA no cambia los niveles de moléculas pro-angiogénicas como VEGF, TGF-b, IL-1 o IL-8 producidas por las células tumorales o endoteliales, sí que induce la sobreexpresión y activación de MMP-9, una metaloproteasa implicada en promover angiogénesis, sugiriendo por tanto que esta proteína puede mediar de forma indirecta los efectos proangiogénicos de tPA. Por otro lado, hemos encontrado que tPA, de forma independiente de su actividad catalítica, promueve directamente la proliferación, migración y tubulogénesis de las células endoteliales. Estos efectos son mediados por la activación en estas células de las rutas de señalización ERK1/2, AKT y JNK. Además, mediante siRNA o inhibidores químicos, hemos encontrado que Annexina A2, Galectina-1 y EGFR son necesarios para la activación de la señalización inducida por tPA en células endoteliales. Finalmente, hemos visto que citoquinas inflamatorias e hipoxia, dos eventos asociados a PDAC y además inductores de angiogénesis, dan lugar a un fuerte incremento de los niveles de tPA en células tumorales pancreáticos. Todos estos datos apoyan un mecanismo de retroalimentación positiva entre estímulos proangiogénicos presentes en las células tumorales y el estroma, y el incremento de la molécula proangiogénica tPA.
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer death in the developed countries and one of the most aggressive human tumors. Despite the key contribution of angiogenesis – the growth of new vessels from pre-existing ones- to the progression and spread of many cancers, its role in PDAC has been poorly characterized. Tissue plasminogen activator (tPA), a multifunctional protein regulating a broad range of cellular functions, has been reported to exert pro-angiogenic effects in in vivo models of PDAC, although the underlying molecular mechanism has not been analyzed. This work aims to elucidate the role of tPA in the angiogenesis of PDAC as well as to identify the factors responsible for tPA increase in pancreatic cancer. First, we demonstrated that tPA pro-angiogenic effects are both indirect and direct. On the one hand, tPA does not change the levels of the pro-angiogenic molecules VEGF, TGF-b, IL-1 or IL-8 produced by pancreatic tumoral cells or endothelial cells, but it is involved in MMP-9 –a potent stimulator of angiogenesis- upregulation and activation in pancreatic and endothelial cells, suggesting that this matrix metalloproteinase can indirectly mediate tPA angiogenic effects. On the other hand, we found that tPA, in a catalytic-independent way, directly promotes endothelial cell proliferation, migration and tubulogenesis. These direct effects of tPA are mediated by activation of ERK1/2, AKT and JNK signaling pathways in endothelial cells. In addition, using siRNA technology or chemical inhibitors, we found that AnnexinA2, Galectin-1 and EGFR are required for tPA-mediated signaling activation in endothelium. Finally, we found that inflammatory cytokines and hypoxia, two hallmarks of PDAC and also angiogenic stimuli, lead to a sharp increase in tPA levels in pancreatic tumoral cells. These data support a feed-back loop between proangiogenic stimuli present in both tumoral and stromal cells and the increase of the proangiogenic molecule tPA.
Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer death in the developed countries and one of the most aggressive human tumors. Despite the key contribution of angiogenesis – the growth of new vessels from pre-existing ones- to the progression and spread of many cancers, its role in PDAC has been poorly characterized. Tissue plasminogen activator (tPA), a multifunctional protein regulating a broad range of cellular functions, has been reported to exert pro-angiogenic effects in in vivo models of PDAC, although the underlying molecular mechanism has not been analyzed. This work aims to elucidate the role of tPA in the angiogenesis of PDAC as well as to identify the factors responsible for tPA increase in pancreatic cancer. First, we demonstrated that tPA pro-angiogenic effects are both indirect and direct. On the one hand, tPA does not change the levels of the pro-angiogenic molecules VEGF, TGF-b, IL-1 or IL-8 produced by pancreatic tumoral cells or endothelial cells, but it is involved in MMP-9 –a potent stimulator of angiogenesis- upregulation and activation in pancreatic and endothelial cells, suggesting that this matrix metalloproteinase can indirectly mediate tPA angiogenic effects. On the other hand, we found that tPA, in a catalytic-independent way, directly promotes endothelial cell proliferation, migration and tubulogenesis. These direct effects of tPA are mediated by activation of ERK1/2, AKT and JNK signaling pathways in endothelial cells. In addition, using siRNA technology or chemical inhibitors, we found that AnnexinA2, Galectin-1 and EGFR are required for tPA-mediated signaling activation in endothelium. Finally, we found that inflammatory cytokines and hypoxia, two hallmarks of PDAC and also angiogenic stimuli, lead to a sharp increase in tPA levels in pancreatic tumoral cells. These data support a feed-back loop between proangiogenic stimuli present in both tumoral and stromal cells and the increase of the proangiogenic molecule tPA.
Keywords
Activador tisular del plasminógeno, angiogénesis, cáncer de pancreas, células endoteliales, rutas de señalización, MMP-9, hipoxia, cell signalling pathways, hypoxia, cytokines
Subjects
616.3 - Pathology of the digestive system. Dentistry
Publisher
Universitat Pompeu Fabra
