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Secondly, like other growth factors discussed in this review, it may stimulate secretion of VEGF from the same or surrounding tumor cells in an autocrine or paracrine fashion.Third, it may interact directly with endothelial cells in two ways: by acting as a mitogen in advanced glioma malignancy despite its physiologic role as an inhibitor of proliferation or by participating in the resolution phase of angiogenesis in gliomas by inducing endothelial cell quiescence and by increasing levels of secretion of basement membrane proteins.The immunohistochemical studies, mRNA expression, and in vitro and in vivo studies discussed herein suggest a pattern of involvement of these growth factors in the progression of malignant gliomas in which increased levels of these tumorderived growth factors andor their cognate receptors mediate their angiogenic effects in three primary ways: by direct endothelial action and tube formation; by indirect endothelial stimulation through increasing VEGF or other growth Vitamin B6 factor expression from tumor or endothelial cells, or both; and by upregulation of key proteases on endothelial cells to remodel surrounding ECM, permitting endothelial cell migration.Taken together, the process of glioma angiogenesis appears to depend on an array of growth factors.Br J Cancer, Jennings MT, Hart CE, Commers PA, Whitlock JA, Martincic D, Maciunas RJ, Moots PL, Shehab TM: Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of plateletderived growth factor.Press RD, Misra A, Gillaspy G, Samols D, Goldthwait DA: Control of the expression of csis mRNA in human glioblastoma cells by phorbol ester and transforming growth factor beta. Fajardo LF, Prionas SD, Kwan HH, Kowalski J, Allison AC: Transforming Growth Factor beta induces angiogenesis in vivo with a threshold pattern.Baird A, Durkin T: Inhibition of endothelial cell proliferation by type betatransforming growth factor: interactions with acidic and basic broblast growth factors.FraterSchroder M, Muller G, Birchmeier W, Bohlen P: Transforming growth factorbeta inhibits endothelial cell proliferation.Heimark RL, Twardzik DR, Schwartz SM: Inhibition of endothelial regeneration by typebeta transforming growth factor from platelets.RayChaudhury A, DAmore PA: Endothelial cell regulation by transforming growth factorbeta.Pepper MS: Transforming growth factorbeta: vasculogenesis, angiogenesis, and vessel wall integrity.Pepper MS, Vassalli JD, Orci L, Montesano R: Biphasic effect of transforming growth factorbeta on in vitro angiogenesis.Icariin Starksen NF, Harsh GR, Gibbs VC, Williams LT: Regulated expression of the plateletderived growth factor A chain gene in microvascular endothelial cells.Kavanaugh WM, Harsh GR, Starksen NF, Rocco CM, Williams LT: Transcriptional regulation of the A and B chains of plateletderived growth factor in microvascular endothelial cells.Battegay EJ, Raines EW, Seifert RA, BowenPope DF, Ross R: TGFbeta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop.Helseth E, Unsgaard G, Dalen A, Vik R: The effects of type beta transforming growth factor on proliferation and epidermal growth factor receptor expression in a human glioblastoma line.Koochekpour S, Merzak A, Pilkington GJ: Vascular endothelial growth factor production is stimulated by gangliosides and TGFbeta isoforms in human glioma cells in vitro.Saadeh PB, Mehrara BJ, Steinbrech DS, Dudziak ME, Greenwald JA, Luchs JS, Spector JA, Ueno H, Gittes GK, Longaker MT: Transforming growth factorbeta modulates the expression of vascular endothelial growth factor by osteoblasts.Donovan D, Harmey JH, Toomey D, Osborne DH, Redmond HP, BouchierHayes DJ: TGF beta regulation of VEGF production by breast cancer cells.Bodey B, Bodey B Jr, Siegel SE, Kaiser HE: Upregulation of endoglin expression during childhood brain tumorrelated angiogenesis: Antiangiogenic therapy.Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP: Defective angiogenesis in mice lacking endoglin.Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M: Endoglin is a component of the transforming growth factorbeta receptor system in human endothelial cells.Black, Longwood Medical Research Center, Room, Longwood Avenue, Boston, MA, USA; Fax; Email: rhouddou.thc.harvard.edu

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