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

Oncogene volume 20, pages 7293–7300 (2001)Cite this article

Abstract

Tumor neovascularization is controlled by a balance between positive and negative effectors, whose production can be regulated by oncogenes and tumor suppressor genes. The aim of this study was to investigate whether the angiogenic potential of tumors could also be controlled by p73, a gene homologous to the tumor suppressor p53, whose involvement in tumor angiogenesis is known. We have studied the production of proangiogenic (VEGF, FGF-2, PIGF and PDGF) and antiangiogenic (TSP-1) factors in two p73 overexpressing clones obtained from the human ovarian carcinoma cells A2780. TSP-1 was downregulated in both clones compared to mock transfected cells, both at mRNA and protein level. Conversely, both clones showed an increased production of VEGF 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 more angiogenic than parental cells, as shown in vitro by their increased chemotactic activity for endothelial cells, and in vivo by the generation of more vascularized tumors. These findings suggest a potential role of p73 in tumor angiogenesis.

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Acknowledgements

We would like to thank GL Semenza (Baltimore, MD, USA) and P Bornstein (Seattle, WA, USA) for the VEGF and TSP-1 promoter constructs, B Vogelstein (Baltimore, MD) for HCT116+/+ and HCT116 −/−, A Vecchi (Milan, Italy) for the anti-CD31 antibody, M Martinelli for in vivo experiments, and E Scanziani (Milan, Italy) for helpful comments on the histochemical analysis of tumors. This work was partially supported by grants from the Italian Association for Cancer Research (AIRC), and the Italian Foundation for Cancer Research (FIRC). F Vikhanskaya is a visiting scientist from the Institute of Cytology (Russian Accademy of Sciences), St. Petersburg, Russia.

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Author notes

  1. Faina Vikhanskaya and Maria R Bani: F Vikhanskaya and MR Bani contributed equally to this work

Authors and Affiliations

  1. Department of Oncology, Mario Negri Institute for Pharmacological Research, Milano, 20157, Italy

    Faina Vikhanskaya, Mirko Marabese & Massimo Broggini

  2. Istituto di Anatomia Patologica Veterinaria e Patologia Aviare, Università degli Studi, Milano, 20133, Italy

    Roberta Ceruti & Gabriele Ghisleni

  3. Department of Oncology, Mario Negri Institute for Pharmacological Research, Bergamo, 24125, Italy

    Maria R Bani, Patrizia Borsotti, Carmen Ghilardi, Roberta Ceruti, Raffaella Giavazzi & Giulia Taraboletti

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  1. Faina Vikhanskaya
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  2. Maria R Bani
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Correspondence to Giulia Taraboletti.

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Vikhanskaya, F., Bani, M., Borsotti, P. et al. p73 overexpression increases VEGF and reduces thrombospondin-1 production: implications for tumor angiogenesis. Oncogene 20, 7293–7300 (2001). https://doi.org/10.1038/sj.onc.1204896

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