transforming-growth-factor-beta and Polyomavirus-Infections

Polyoma BK virus (PBK) is a prevalent human specific virus and the cause of several malignancies in human. The main mechanisms used by PBK to induce/stimulate human cancers are yet to be clarified but it has been proposed that PBK may use several mechanisms to induce/stimulate cancers in human including attenuation of immune responses via up-regulation of immunosuppressor molecules. Transforming growth factor beta (TGF-β) is a key multifunctional factor from modulation of immunosurveillance to angiogenesis. The key roles of TGF-β in the progression of Th17 and T regulatory subsets, the most important immune cells involved in development of cancers, have been demonstrated. Thus, this review article aims to describe the mechanisms used by PBK in induction/stimulation of human cancers in TGF-β dependent manner..

Topics: BK Virus; Carcinogenesis; Humans; Immune Tolerance; Neoplasms; Polyomavirus Infections; Transforming Growth Factor beta; Tumor Virus Infections

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty-eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real-time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)-2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)-β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF-β, but not IL-2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF-β and IL-6 mRNA. After adjusting for age and sex in the regression model, both age and TGF-β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF-β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF-β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients.

Topics: BK Virus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Prognosis; Real-Time Polymerase Chain Reaction; Risk Factors; Transforming Growth Factor beta; Tumor Virus Infections; Viral Load; Viremia

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.

Topics: Animals; BK Virus; Cell Line, Transformed; Cell Transformation, Viral; Epithelial Cells; Leukocytes, Mononuclear; Male; Mice; Mice, Nude; Neoplasm Regression, Spontaneous; Neoplasm Transplantation; Neovascularization, Pathologic; Polyomavirus Infections; Sarcoma, Kaposi; Transforming Growth Factor beta; Transforming Growth Factor beta1; Tumor Virus Infections