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  • Original Paper
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Human endothelial cells expressing polyoma middle T induce tumors

Oncogene volume 19, pages 3632–3641 (2000)Cite this article

Abstract

The middle T oncogene of murine polyomavirus (PymT) rapidly transforms and immortalizes murine embryonic endothelial cells (EC), leading to the formation of vascular tumors in newborn mice, by recruitment of host, non-transformed EC. These tumors are reminiscent of human vascular tumors like cavernous hemangioma, Kaposi's sarcoma or those characterizing Kasabach-Merrit syndrome. Here we investigate the in vitro and in vivo behavior of human primary umbilical cord vein EC expressing PymT. While PymT has been unable to transform human fibroblasts in earlier experiments or controls done here, mT expressing EC (PymT-EC) derived by infection with pLX-PymT retrovirus induce hemangiomas in nu/nu mice. These tumors contain not only human cells but also recruited mouse EC as shown by the presence of human and murine CD31 positive EC. In vitro analysis shows that PymT-EC retain endothelial specific markers like CD31, Von Willebrand factor, and VE-cadherin, and reach the confluence without signs of overgrowth. They are also responsive to vascular endothelial growth factor-A. However, their proliferation rate is increased. The balance between urokinase-type plasminogen activator and plasminogen activator inhibitor-1 is modified; RNA and catalytic activity for the former are elevated while PAI-1 RNA is reduced. In contrast with murine model, where the PymT EC cells become immortal, the effects induced by PymT in human EC are transient. After 12–15 passages, human PymT EC stop proliferating, assume a senescent phenotype, and lose the ability to induce hemangiomas. At the same time both the amount of middle T protein and the level of activation of pp60c-src lower.

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Acknowledgements

We are particularly grateful to B Schaffhausen (Tufts University, Boston, USA) for antibodies anti-PymT and for critically reading and reviewing of the manuscript. The authors thank: Drs E Dejana, A Vecchi (Istituto ‘Mario Negri’, Milano, Italy) for Ab anti-human VE-cadherin and anti-murine CD31; Prof F Blasi (Ospedale San Raffaele-Dibit, Milano, Italy) for uPA and PAI-1 cDNAs; Dr M Risio (Institute for Cancer Research and Treatment, Ordine del Mauriziano, Candiolo, Italy) for his suggestions and encouragement in histological analysis; Prof MF DiRenzo (Institute for Cancer Research and Treatment, Candiolo, Italy) and Prof A Mantovani (Istituto ‘Mario Negri’, Milano, Italy) for their fruitful discussions. This study was supported by Italian Association for Cancer Research (A.I.R.C.), Istituto Superiore di Sanità (Programma Nazionale di Ricerca sull'AIDS: Patogenesi, immunità e vaccino per l'AIDS (40B.19) e Patologia, clinica e terapia dell'AIDS (30B.9), and Program on Tumor Therapy), Ministero dell'Università e della Ricerca Scientifica e Tecnologica (60% and Programma di Ricerca di Rilevante Interesse Nazionale-1998 and 1999), and Regione Piemonte.

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  1. Institute for Cancer Research and Treatment (I.R.C.C.), Candiolo (Torino), 10060, Italy

    Luca Primo, Cristina Roca, Chiara Ferrandi & Federico Bussolino

  2. Department of Genetics, Biology and Biochemistry, School of Medicine, University of Torino, Torino, 10100, Italy

    Luca Primo, Cristina Roca, Chiara Ferrandi & Federico Bussolino

  3. Department of Experimental Oncology, European Institute of Oncology, Milano, 20100, Italy

    Luisa Lanfrancone

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Primo, L., Roca, C., Ferrandi, C. et al. Human endothelial cells expressing polyoma middle T induce tumors. Oncogene 19, 3632–3641 (2000). https://doi.org/10.1038/sj.onc.1203708

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