p73 overexpression increases VEGF and reduces thrombospondin-1 production:implications for tumor angiogenesis

Tumor neovascularization is controlled by a balance between positive and ne gative effectors, whose production can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate whether the angi ogenic potential of tumors could also be controlled by p73, a gene homologo us to the tumor suppressor p53, whose involvement in tumor angiogenesis is known. We have studied the production of proangiogenic (VEGF, FGF-2, PIGF a nd PDGF) and antiangiogenic (TSP-1) factors in two p73 overexpressing clone s obtained from the human ovarian carcinoma cells A2780. TSP-1 was downregu lated in both clones compared to mock transfected cells, both at mRNA bind protein level. Conversely, both clones showed an increased production of VE GF mRNA and protein. For both TSP-1 and VEGF, regulation of expression was partially due to modulation of the promoter activity, and was dependent on p53 status. Production of the other angiogenic factors FGF-2, PIGF and PDGF -B was also increased in p73 overexpressing clones. The two clones were mor e angiogenic than parental cells, as shown in vitro by their increased chem otactic activity for endothelial cells, and in vivo by the generation of mo re vascularized tumors. These findings suggest a potential role of p73 in t umor angiogenesis.