Figure 1.

A schematic overview of the molecular network involved in VSV oncoselectivity. Binding of growth factors to the receptor tyrosine kinase (RTK) activates the receptor complex, which in turn recruits and activates PI3K. Activated PI3K converts PIP2 to PIP3, which subsequently mediates the phosphorylation of AKT. Tumor suppressor PTEN negatively regulates the pathway by removing the 3-phosphate from PIP3, converting it back to PIP2. PTEN is crucial for the activation of IRF3, its import into the nucleus and production of IFN-β. Loss of PTEN leads to over-activation of AKT and subsequently mTOR, which is associated with uncontrolled cell growth, proliferation, and survival. PTEN loss leads also to the development of cancer stem cells (CSCs) and an impaired cellular responses to viral infection. Up-regulation of LDLR in ovarian carcinomas enables VSV to enter cells with altered PTEN function through LDLR. Abbreviations: PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (4,5)-bisphosphate); PIP3, phosphatidylinositol (3,4,5)-trisphosphate); AKT, serine/threonine kinase; IRF3, interferon regulatory factor-3; mTOR, mammalian target of rapamycin; LDLR, low-density lipoprotein receptor. See text for further details.