title: Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer.
abstract: Cancer is an increasing and major problem after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of cyclosporine (CsA) on VEGF expression. Using a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving PKC zeta and PKC delta isoforms. Moreover, CsA promoted the association of PKC zeta and PKC delta with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1 dependent. Furthermore, CsA-induced and PKC-Sp1-mediated VEGF transcriptional activation was partially inhibited by von Hippel-Lindau protein. CsA also promoted the progression of human renal tumors in vivo, wherein VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size and VEGF mRNA expression and also enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer.
authors.affiliation: Division of Nephrology, Children's Hospital Boston, Boston, MA 02115, USA.
authors.forename: Aninda
authors.initials: A
authors.lastname: Basu
authors.forename: Alan G
authors.initials: AG
authors.lastname: Contreras
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.forename: Evelyn
authors.initials: E
authors.lastname: Flynn
authors.forename: Liling
authors.initials: L
authors.lastname: Zeng
authors.forename: Herbert T
authors.initials: HT
authors.lastname: Cohen
authors.forename: David M
authors.initials: DM
authors.lastname: Briscoe
authors.forename: Soumitro
authors.initials: S
authors.lastname: Pal
mesh_terms: D000818:Animals; D065095:Calcineurin Inhibitors; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008113:Liver Neoplasms / Q000139:chemically induced*; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D016377:Organ Transplantation / Q000009:adverse effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D042461:Vascular Endothelial Growth Factor A; D016572:Cyclosporine