title: Survivin expression promotes VEGF-induced tumor angiogenesis via PI3K/Akt enhanced β-catenin/Tcf-Lef dependent transcription.
abstract: Early in cancer development, tumour cells express vascular endothelial growth factor (VEGF), a secreted molecule that is important in all stages of angiogenesis, an essential process that provides nutrients and oxygen to the nascent tumor and thereby enhances tumor-cell survival and facilitates growth. Survivin, another protein involved in angiogenesis, is strongly expressed in most human cancers, where it promotes tumor survival by reducing apoptosis as well as favoring endothelial cell proliferation and migration. The mechanisms by which cancer cells induce VEGF expression and angiogenesis upon survivin up-regulation remain to be fully established. Since the PI3K/Akt signalling and β-catenin-Tcf/Lef dependent transcription have been implicated in the expression of many cancer-related genes, including survivin and VEGF, we evaluated whether survivin may favor VEGF expression, release from tumor cells and induction of angiogenesis in a PI3K/Akt-β-catenin-Tcf/Lef-dependent manner. Here, we provide evidence linking survivin expression in tumor cells to increased β-catenin protein levels, β-catenin-Tcf/Lef transcriptional activity and expression of several target genes of this pathway, including survivin and VEGF, which accumulates in the culture medium. Alternatively, survivin downregulation reduced β-catenin protein levels and β-catenin-Tcf/Lef transcriptional activity. Also, using inhibitors of PI3K and the expression of dominant negative Akt, we show that survivin acts upstream in an amplification loop to promote VEGF expression. Moreover, survivin knock-down in B16F10 murine melanoma cells diminished the number of blood vessels and reduced VEGF expression in tumors formed in C57BL/6 mice. Finally, in the chick chorioallantoid membrane assay, survivin expression in tumor cells enhanced VEGF liberation and blood vessel formation. Importantly, the presence of neutralizing anti-VEGF antibodies precluded survivin-enhanced angiogenesis in this assay. These findings provide evidence for the existance of a posititve feedback loop connecting survivin expression in tumor cells to PI3K/Akt enhanced β-catenin-Tcf/Lef-dependent transcription followed by secretion of VEGF and angiogenesis.
authors.forename: Jaime G
authors.initials: JG
authors.lastname: Fernández
authors.forename: Diego A
authors.initials: DA
authors.lastname: Rodríguez
authors.forename: Manuel
authors.initials: M
authors.lastname: Valenzuela
authors.forename: Claudia
authors.initials: C
authors.lastname: Calderon
authors.forename: Ulises
authors.initials: U
authors.lastname: Urzúa
authors.forename: David
authors.initials: D
authors.lastname: Munroe
authors.forename: Carlos
authors.initials: C
authors.lastname: Rosas
authors.forename: David
authors.initials: D
authors.lastname: Lemus
authors.forename: Natalia
authors.initials: N
authors.lastname: Díaz
authors.forename: Mathew C
authors.initials: MC
authors.lastname: Wright
authors.forename: Lisette
authors.initials: L
authors.lastname: Leyton
authors.forename: Julio C
authors.initials: JC
authors.lastname: Tapia
authors.affiliation: Laboratorio de Comunicaciones Celulares, Centro de Estudios Moleculares de la Célula (CEMC), Programa de Biología Celular y Molecular, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile. aquest@med.uchile.cl.
authors.forename: Andrew Fg
authors.initials: AF
authors.lastname: Quest
mesh_terms: D000818:Animals; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000077022:Survivin; D014158:Transcription, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt