title: Tumor-host interaction mediates the regression of BK virus-induced vascular tumors in mice: involvement of transforming growth factor-beta1.
abstract: Several sexually transmitted viruses have been associated with the development of Kaposi's sarcoma (KS), a highly vascularized multi-focal 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 experimental model to test whether BKV may be involved in the pathogenesis of KS. For this purpose, we transformed primary and spontaneously 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 7-30 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-beta1 (TGF-beta1) antibody. Northern blot analysis revealed that BKV-transformed cells express a greater amount of TGF-beta1 RNA than normal murine endothelial cells. Besides, TGF-beta1 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. Over-expression of TGF-beta1 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 us to test whether production of TGF-beta1 is associated with spontaneous KS regression in human patients. In this case, KS regression could be induced or accelerated by any means that enhances TGF-beta1 production at the tumor site.
authors.affiliation: Department of Experimental and Diagnostic Medicine, Section of Microbiology, University of Ferrara, Ferrara, Italy.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Corallini
authors.forename: Laura
authors.initials: L
authors.lastname: Possati
authors.forename: Cecilia
authors.initials: C
authors.lastname: Trabanelli
authors.forename: Enrico
authors.initials: E
authors.lastname: Giraudo
authors.forename: Romina
authors.initials: R
authors.lastname: Rocchetti
authors.forename: Simona
authors.initials: S
authors.lastname: Talevi
authors.forename: Antonella
authors.initials: A
authors.lastname: Caputo
authors.forename: Federico
authors.initials: F
authors.lastname: Bussolino
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Barbanti-Brodano
mesh_terms: D000818:Animals; D001739:BK Virus; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D004847:Epithelial Cells / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009365:Neoplasm Regression, Spontaneous / Q000276:immunology*; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D027601:Polyomavirus Infections; D012514:Sarcoma, Kaposi / Q000821:virology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014412:Tumor Virus Infections
chemical_list: C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1