Molecular Events Implicated in Brain Tumor Angiogenesis and Invasion

Zagzag, David; Friedlander, David R.; Margolis, Ben; Grumet, Martin; Semenza, Gregg L.; Simons, Jonathan W.; Holash, Jocelyn; Wiegand, Stanley J.; Yancopouloš, George D.

doi:10.1159/000028975

Cited by 92 publications

(65 citation statements)

References 19 publications

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“…Human glioblastoma is a richly vascularised tumour (Zagzag et al, 2000) that expresses and actively releases in the vicine tissues substantial amounts of factors promoting new vessel growth (Guerin and Laterra, 1997). As a counterproof of such biological attitude of glioblastoma, we also found that VEGF is actively released by A172, U87MG and U373MG glioblastoma cells in the tissue culture media.…”

Section: Discussionmentioning

confidence: 58%

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

et al. 2006

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Tumour growth is tightly related to new blood vessel formation, tissue remodelling and invasiveness capacity. A number of tissular factors fuel the growth of glioblastoma multiforme, the most aggressive brain neoplasm. In fact, gene array analyses demonstrated that the proapoptotic cytokine tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) inhibited mRNA expression of VEGF, along with those of matrix metalloproteinase-2 (MMP-2), its inhibitor tissue inhibitor of matrix metalloproteinases-2 (TIMP-2), as well as the tumour invasiveness-related gene secreted protein acid rich in cysteine (SPARC) in different human glioblastoma cell lines. Particularly, VEGF mRNA and protein expression and release from glioblastoma cells were also inhibited by TRAIL. The latter also exerted antimitogenic effects on human umbilical vein endothelial cells (HUVECs). With the same cells, TRAIL inhibited new vessel formation in the in vitro matrigel model, as well as it exerted powerful inhibition of blood vessel formation induced by an angiogenic cocktail administered in subcutaneous pellets in vivo in the C57 mouse. Moreover, the expression of MMP-2, its inhibitor TIMP-2 and the tumour invasiveness-related protein SPARC were effectively inhibited by TRAIL in glioblastoma cell lines. In conclusion, our data indicate that TRAIL inhibits the orchestra of factors contributing to glioblastoma biological aggressiveness. Thus, the TRAIL system could be regarded as a molecular target to exploit for innovative therapy of this type of tumour.

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Section: Discussionmentioning

confidence: 58%

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

et al. 2006

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“…We and others have reported previously that FAK protein and activity (based on phosphorylation of Tyr 397 ) are elevated in grades III and IV malignant astrocytoma tumors (anaplastic astrocytoma and glioblastoma, respectively), compared with the normal brain (7,13). We have also shown that the overexpression of wild-type FAK promotes soft agar growth of glioblastoma cells (14), the expression of the mutant FAK397F inhibits soft agar growth of these cells (15), and that FAK is sufficient to promote Ras activity in glioblastoma cells propagated in aggregate suspension or as a monolayer (15).…”

Section: Fakmentioning

confidence: 90%

“…FIG. 13. Elevated expression of the transcription factor KLF8 with expression of wild-type FAK in glioblastoma cells propagated in vitro and in vivo.…”

Section: Ubiquitin-dependent Degradation Of P27mentioning

confidence: 99%

p27Kip1 and Cyclin D1 Are Necessary for Focal Adhesion Kinase Regulation of Cell Cycle Progression in Glioblastoma Cells Propagated in Vitro and in Vivo in the Scid Mouse Brain

Ding

Grammer

Nelson

et al. 2005

Journal of Biological Chemistry

116

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We have reported previously that the expression of focal adhesion kinase (FAK) is elevated in glioblastomas and that expression of FAK promotes the proliferation of glioblastoma cells propagated in either soft agar or in the C.B.17 severe combined immunodeficiency (scid) mouse brain. We therefore determined the effect of FAK on cell cycle progression in these cells. We found that overexpression of wild-type FAK promoted exit from G 1 in monolayer cultures of glioblastoma cells, enhanced the expression of cyclins D1 and E while reducing the expression of p27 Kip1 and p21 Waf1 , and enhanced the kinase activity of the cyclin D1-cyclin-dependent kinase-4 (cdk4) complex. Transfection of the monolayers with a FAK molecule in which the autophosphorylation site is mutated (FAK397F) inhibited exit from G 1 and reduced the expression of cyclins D1 and E while enhancing the expression of p27 Kip1 and p21 Waf1 . Small interfering RNA (siRNA)-mediated down-regulation of cyclin D1 inhibited the enhancement of cell cycle progression observed on expression of wild-type FAK, whereas siRNA-mediated down-regulation of cyclin E had no effect. siRNAmediated down-regulation of p27Kip1 overcame the inhibition of cell cycle progression observed on expression of FAK397F, whereas down-regulation of p21Waf1 had no effect. These results were confirmed in vivo in the scid mouse brain xenograft model in which propagation of glioblastoma cells expressing FAK397F resulted in a 50% inhibition of tumor growth and inhibited exit from G 1 . Taken together, our results indicate that FAK promotes proliferation of glioblastoma cells by enhancing exit from G 1 through a mechanism that involves cyclin D1 and p27 Kip1 .FAK 1 is a nonreceptor cytoplasmic tyrosine kinase. It has been shown to be activated on clustering of integrin receptors in the cell membrane or by the ligation of multiple growth factor receptors (1-3). Activation occurs through phosphorylation of Tyr 397 , either through autophosphorylation or Src-induced phosphorylation (4). Clustering of integrin receptors occurs during cell attachment, and the receptors localize to focal contacts (early adhesion complexes) where, in a temporally related manner, a signaling complex is assembled which includes FAK as well as cellular Src and other kinases, cytoskeletal proteins, and adaptor molecules (3, 5, 6). In nonmalignant and nontransformed cells, this localization of FAK to focal contacts or focal adhesions (mature adhesion complexes) has been shown to be necessary for its activation, indicating that FAK activation is regulated by integrin receptor engagement or cell adhesion in these cells. In contrast, in malignant or transformed cells, the activation of FAK does not appear to be regulated solely by cell adhesion or integrin receptor engagement. For example, we have shown the activation of FAK (phosphorylation of Tyr 397 ) in glioblastoma cells propagated in suspension, suggesting that the mechanisms governing the activation of FAK in malignant or transformed cells may differ from those util...

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“…Recruitment or cooption of preexisting blood vessels by tumors, as previously described by Holash and colleagues, may represent one such mechanism (5)(6)(7). Early in tumor development, preexisting vasculature is engaged by growing tumor cells.…”

mentioning

confidence: 92%

Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma

Kim

Serur

Huang

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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291

187

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Molecular Events Implicated in Brain Tumor Angiogenesis and Invasion

Cited by 92 publications

References 19 publications

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

TRAIL inhibits angiogenesis stimulated by VEGF expression in human glioblastoma cells

p27Kip1 and Cyclin D1 Are Necessary for Focal Adhesion Kinase Regulation of Cell Cycle Progression in Glioblastoma Cells Propagated in Vitro and in Vivo in the Scid Mouse Brain

Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma

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