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Carcinogenesis Advance Access published online on July 4, 2003
Carcinogenesis, doi:10.1093/carcin/bgg096
© 2003 by Oxford University Press
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© 2003 Oxford University Press

CANCER BIOLOGY

Tumor-host interaction mediates the regression of BK virus-induced vascular tumors in mice: involvement of transforming growth factor-{beta}1

Alfredo Corallini 1, Laura Possati 2, Cecilia Trabanelli 1, Enrico Giraudo 3, Romina Rocchetti 2, Simona Talevi 2, Antonella Caputo 1, Federico Bussolino 3, and Giuseppe Barbanti-Brodano 1*

1 Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy; Center of Biotechnology, University of Ferrara, Ferrara, Italy
2 Institute of Biomedical Sciences, University of Ancona, Ancona, Italy
3 Department of Genetics, Biology and Biochemistry, Institute for Cancer Research and Treatment, School of Medicine, University of Torino, Candiolo, Italy

* Corresponding author. E-mail: brb{at}.unife.it.

Received 24 July 2002 ; revised 15 April 2003 ; accepted 21 May 2003

Abstract

Several sexually transmitted viruses have been associated with the development of Kaposi's sarcoma (KS), a highly vascularized multifocal neoplasm, characterized by the presence of spindle-shaped and endothelial cells, fibroblasts and macrophages. As BK virus (BKV) sequences were found in 100% of primary KS and 75% of KS cell lines, we established an experimetal model to test whether BKV may be involved in the pathogenesis of KS. To this purpose, we transformed primary and spontaneuosly immortalized murine endothelial cells with BKV or with a plasmid containing BKV early region which encodes BKV T antigen. Murine endothelial cells lost endothelial markers after transformation by BKV and, when inoculated s.c. in nude mice, induced tumors which regressed 7 to 30 days after onset, whereas spontaneously immortalized murine endothelial MHE cells induced progressing tumors which brought the animals to death. Histologic examination showed an initial formation of vessels around the tumors, followed by the appearance of a dense population of fibroblasts and mononuclear cells in the peritumoral tissue. Subsequently, tumors appeared to be infiltrated by mononuclear cells and surrounded by a thick fibrous wall with scattered fibroblasts and without vessels. Areas of necrosis developed in the tumor mass and finally the neoplastic tissue completely degenerated. The medium conditioned by BKV-transformed cells induced proliferation and migration of human fibroblasts and NIH3T3 cells. These effects were inhibited by an anti-transforming growth factor-{beta}1 (TGF-{beta}1) antibody. Northern blot analysis revealed that BKV-transformed cells express a greater amount of TGF-{beta}1 RNA than normal murine endothelial cells. Besides, TGF-{beta}1 was not expressed in progressing tumors induced by spontaneously immortalized endothelial MHE cells, whereas it was highly expressed during the regression of tumors induced by BKV-transformed MHE and primary endothelial cells. Overexpression of TGF-{beta}1 may be responsible for the mononuclear cell infiltration, inhibition of angiogenesis and formation of the fibrotic wall around tumors, inducing tumor regression through tumor cell necrosis and nutritional starvation. These results prompt to test whether production of TGF-{beta}1 is associated to spontaneous KS regression in human patients. In this case, KS regression could be induced or accelerated by any means which enhances TGF-{beta}1 production at the tumor site.


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