Anti-tumor activity of cytokines against opportunistic vascular tumors in mice

Abstract

Polyoma middle T (PmT)-transformed endothelial cells may represent a unique murine model for human opportunistic vascular tumors. The present study was designed to evaluate the anti-tumor potential of a panel of 13 cytokines against murine PmT-transformed endothelial cells. Interferon gamma (IFNγ) and transforming growth factor beta 1 (TGFβ1) substantially decreased in a dose-dependent manner the proliferation of a panel of 6 PmT-transformed cell lines. IFNα and tumor necrosis factor α (TNFα) had marginal anti-proliferative activity, whereas other molecules (interleukins-1, -2, -4, -6 and -13, IFNβ, leukemia inhibitory factor, oncostatin M, granulocyte-macrophage colony-stimulating factor) caused no growth inhibition. IFNγ and TGFβ1 were therefore selected for further analysis of their mechanism of action and in vivo relevance. IFNγ and TGFβ1 reduced the activity of phosphatidylinositol-3-kinase and the production of phosphatidylinositol 3,4-biphosphate, without modifying the tyrosine kinase(s) activity associated with PmT. IFNγ and TGFβ1 were also tested for their ability to modify the in vivo growth of the PmT-transformed endothelial cells H5V in syngeneic C57B1/6 mice. Treatment with IFNα and TGFβ1 significantly delayed tumor growth and increased survival time. In contrast, treatment with IFNα and TNFα failed to prolong survival. In nude mice, IFNα and TGFβ1 1 had a transient effect on tumor growth but no effect on survival, suggesting a contribution of T cells to the in vivo anti-tumor activity of these cytokines.