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IL-6 is an in vitro and in vivo autocrine growth factor for middle T antigen-transformed endothelial cells
E Giraudo1, M Arese, C Toniatti
1Department of Genetics, Biological and Medical Chemistry, University of Torino, Italy.
Abstract:
Murine endothelial cells immortalized with the middle-size Ag of polyomavirus (PmT) cause vascular tumors in syngenic mice by recruitment of host normal endothelial cells. This pathogenic process is similar to that occurring in Kaposi's sarcoma, in which the core of the lesion is constituted by "spindle cells," which recruit normal vascular mesenchymal cells. In murine endothelial cells, PmT induces modification of the expression of genes, including that of IL-6. Since IL-6 is a pleiotrophic cytokine that also regulates endothelial cell functions related to angiogenesis, we studied the relevance of IL-6 in the tumorigenicity of PmT-endothelial cells. In vitro studies demonstrated that the spontaneous PmT-endothelial cell proliferation rate was slow during the first 6 days of culture and then increased rapidly and paralleled the IL-6 release. The addition of recombinant IL-6 during the first days of culture induced a marked proliferation in a dose-dependent manner. PmT-endothelial cells expressed on their surface a high-affinity binding site for IL-6 constituted by both IL-6Ralpha and gp130 transmembrane receptors. The growth-promoting effect of exogenous IL-6 or that released by PmT-endothelial cells was abrogated by mAbs anti-IL-6Ralpha, whereas a mAb recognizing the endothelial cell CD31 molecule was inactive. 15A7 mAb anti-murine IL-6Ralpha was also active in vivo, reducing the number of metastases forming after transplantation of PmT-endothelial cells in DBA/2 mice. 15A7 mAb also increased the survival of mice bearing vascular tumors. We conclude that IL-6 is involved in the progression of vascular tumors induced by PmT, and that the blockage of IL-6-mediated intercellular circuits could be useful in the management of human vascular tumors, including Kaposi's sarcoma.
Insights
Interleukin-6 (IL-6) drives the progression of vascular tumors induced by polyomavirus middle tumor antigen (PmT) in mice. Blocking IL-6 signaling with antibodies significantly reduced tumor metastasis and improved survival, suggesting therapeutic potential for human vascular tumors.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Polyomavirus middle tumor antigen (PmT)-immortalized murine endothelial cells induce vascular tumors by recruiting host cells, mirroring Kaposi's sarcoma pathogenesis.
- PmT alters gene expression in endothelial cells, including Interleukin-6 (IL-6), a cytokine known to regulate angiogenesis.
Purpose of the Study:
- To investigate the role of IL-6 in the tumorigenicity of PmT-endothelial cells.
- To assess the therapeutic potential of targeting IL-6 signaling in PmT-induced vascular tumors.
Main Methods:
- In vitro proliferation assays of PmT-endothelial cells with and without recombinant IL-6.
- Analysis of IL-6 receptor expression (IL-6Ralpha and gp130) on PmT-endothelial cells.
- In vivo studies using anti-IL-6Ralpha monoclonal antibodies (mAbs) to evaluate tumor metastasis and survival in mice.
Main Results:
- PmT-endothelial cell proliferation correlated with IL-6 release; exogenous IL-6 enhanced proliferation dose-dependently.
- PmT-endothelial cells express high-affinity IL-6 receptors.
- Anti-IL-6Ralpha mAbs, but not anti-CD31 mAbs, inhibited IL-6's growth-promoting effects in vitro.
- In vivo, anti-murine IL-6Ralpha mAb reduced metastasis and increased survival in mice with vascular tumors.
Conclusions:
- IL-6 is a critical mediator in the progression of PmT-induced vascular tumors.
- Targeting IL-6-mediated signaling pathways offers a potential therapeutic strategy for vascular tumors, including Kaposi's sarcoma.