Browsing by Author "Owen, Gareth"
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Item Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation(Multidisciplinary Digital Publishing Institute (MDPI), 2019) Arce, Maximiliano; Pinto, Mauricio; Galleguillos, Macarena; Muñoz, Catalina; Lange, Soledad; Ramirez, Carolina; Erices, Rafaela; González, Pamela; Velásquez, Ethel; Tempio, Fabián; López, Mercedes; Salazar-Onfray, Flavio; Cautivo, Kelly; Kalergis, Alexis; Cruz, Sebastián; Lobos-González, Lorena; Lladser, Álvaro; Valenzuela, Guillermo; Olivares, Nixa; Sáez, Claudia; Koning, Tania; Sánchez, Fabiola; Fuenzalida, Patricia; Godoy, Alejandro; Contreras, Pamela; Leyton, Lisette; Lugano, Roberta; Dimberg, Anna; Quest, Andrew; Owen, GarethHypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.Item Expression of teneurins is associated with tumor differentiation and patient survival in ovarian cancer(PLoS, 2017) Graumann, Rebecca; Di Capua, Gabriella A.; Oyarzún, Juan; Vásquez, Marcos A.; Liao, Christine; Brañes, Jorge A.; Roa, Iván; Casanello, Paola; Corvalán, Alejandro H.; Owen, Gareth; Delgado, Iris; Uwe, Zangemeister-Wittke; Ziegler, AnnemarieTeneurins are a family of highly conserved pair-rule proteins involved in morphogenesis and development of the central nervous system. Their function in adult tissues and in disease is largely unknown. Recent evidence suggests a role for dysregulated expression of Teneurins in human tumors, but systematic investigations are missing. Here, we investigated Teneurin-2 and Teneurin-4 expression in various cancer cell lines and in ovarian tumor tissues. Teneurin-2 and Teneurin-4 were expressed in most of the breast cancer cell lines tested. Teneurin-4 was also detected in ovarian cancer cell lines, and throughout ovarian tumors and normal ovary tissue. Ovarian tumors with low Teneurin-4 expression showed less differentiated phenotypes and these patients had shorter mean overall survival. Similarly, Teneurin-2 expression correlated with overall survival as well, especially in patients with serous tumors. In the various cell lines, 5-Aza-cytidine-induced changes in DNA methylation did not alter expression of Teneurin-2 and Teneurin-4, despite the existence of predicted CpG islands in both genes. Interestingly, however, we found evidence for the control of Teneurin-2 expression by the oncogenic growth factor FGF8. Furthermore, we identified multiple transcript splicing variants for Teneurin-2 and Teneurin-4, indicating complex gene expression patterns in malignant cells. Finally, downregulation of Teneurin-4 expression using siRNA caused a cell-type dependent increase in proliferation and resistance to cisplatin. Altogether, our data suggest that low Teneurin-4 expression provides a growth advantage to cancer cells and marks an undifferentiated state characterized by increased drug resistance and clinical aggressiveness. We conclude that Teneurin-2 and Teneurin-4 expression levels could be of prognostic value in ovarian cancer.