The finding that IFP is also elevated in very small tumors suggests that the delivery of large anticancer agents to micrometas tasis could be impeded by interstitial hypertension.Role of interstitial pressure and convection.Click on Request Permissions which will take you to the Copyright Clearance Centers Downloaded from cancerres.aacrjournals.org on August. American Association for Cancer Research. Tumor progression, particularly in aggressive and malignant tumors, is associated with the induction of angiogenesis, a process termed the angiogenic switch.Therefore, we tested whether PTEN regulates tumor progression by modulating angiogenesis.UMG glioma cells stably Glimepiride reconstituted with PTEN cDNA were tested for growth in a nude mouse orthotopic brain tumor model.We observed that the reconstitution of wildtype PTEN had no effect on in vitro proliferation but dramatically Ibuprofen decreased tumor growth in vivo and prolonged survival in mice implanted intracranially with these tumor cells.These effects were not observed in tumors reconstituted with a lipid phosphatase inactive GE mutant of PTEN, a result that provides evidence that the lipid phosphatase activity of PTEN regulates the angiogenic response in vivo.These data provide evidence that PTEN regulates tumorinduced angiogenesis and the progression of gliomas to a malignant phenotype via the regulation of phosphoinositidedependent signals.T he reversible phosphor ylation of proteins and lipids is critical to the control of signal transduction in mammalian cells and is regulated bykinases and phosphatases was identified as a dual specificity phosphatase and has been shown to dephosphor ylate inositol phospholipids. The PTEN gene is mutated in of highgrade gliomas as well as prostate, endometrial, breast, lung, and other tumors. The sequence of the extreme C terminus of PTEN suggests a function in binding PDZ domaincontain ing proteins.PTEN is a dual specificity phosphatase that displays a pronounced preference for acidic substrates. Importantly, PTEN possesses lipid phosphatase activ ity, preferentially dephosphor ylating phosphoinositides at the D position of the inositol ring.It is the only enzyme known to dephosphor ylate the D position in inositol phospholipids, suggesting that PTEN may function as a direct antagon ist of phosphatidylinositol k inase P dependent signaling. However, despite progress in understanding the biochemistryof PTEN, the role of this phosphatase in tumor progression, as it relates to its diverse ef fects on cell grow th, angiogenesis, andyor survival, remains unclear.Tumor progression is associated with angiogenesis, the formation of new blood vessels from ex isting vascular structures, with increases in microvessel density. For tumor growth to occur, tumor dormancy must be broken, an event termed the angiogenic switch.During angiogenesis endothelial cells are induced to degrade the basement membrane of ex isting vessels, break away, and migrate to the site of the tumor, where they proliferate to form linear structures that differentiate to form blood vessels.Stimulators include the growth factors, vascular endothelial growth factor and basic fibroblast growth factor, and the induction of matrix remodelingvia matrix metalloproteinases, angiostatin, endostatin, tissue inhibitors of metalloproteinases, and others. It has been observed that neovascularization and PTEN mutations are associated with highgrade gliomas and are not observed in lowgrade glial tumors, leading to the hypothesis that these two events may be causally linked.