Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras

Feldkamp, Matthias M.; Lau, Nelson C.; Rak, Janusz; Kerbel, Robert S.; Guha, Abhijit

doi:10.1002/(sici)1097-0215(19990331)81:1<118::aid-ijc20>3.0.co;2-5

Cited by 99 publications

(29 citation statements)

References 19 publications

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“…We thus investigated whether this enhanced in vivo e ect may relate to an additional anti-angiogenic e ect of the agent. Evidence from our laboratory and from others has demonstrated the importance of the angiogenic factor Vascular Endothelial Growth Factor (VEGF) in the pathogenesis of high grade astrocytic tumours (Asano et al, 1995;Feldkamp et al, 1999;Melnyk et al, 1996;Millauer et al, 1996;Saleh et al, 1996). Astrocytomas secrete high levels of the potent and endothelial speci®c angiogenic factor VEGF (Plate et al, 1992), whose expression through increased transcription or enhanced mRNA stability is highly regulated by hypoxia Goldberg and Schneider, 1994;Levy et al, 1996).…”

Section: Discussionmentioning

confidence: 87%

“…L-744,832 results in a dose-dependent increase in the proportion of cells in the G 2 /M fraction of the cycle, as well as a reduction in BrdU incorporation. Numeric data is provided in Table 1 robust hypoxic induction of both VEGF mRNA and protein (Feldkamp et al, 1999). While the levels of VEGF mRNA were minimally a ected by exposure to the agent (Figure 9d), levels of secreted protein were signi®cantly reduced in cells grown in as little as 10 mM drug.…”

Section: Morphological Changes In Cells Treated With Ftismentioning

confidence: 98%

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Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras.GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their e ect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its e ect. L-744,832 demonstrates both cytostatic and cytotoxic e ects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in highgrade astrocytomas (EGFRvIII/p140 EGF-R ) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchoragedependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G 1 /M and G 2 /S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21 WAF1/CIP1 , but this induction is not necessary for the cell cycle inhibitory e ects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic e ects.

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Section: Discussionmentioning

confidence: 87%

Section: Morphological Changes In Cells Treated With Ftismentioning

confidence: 98%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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“…We and others have shown that the ras pathway plays an important role in erbB signaling (Ben- Levy et al, 1994;Yen et al, 1997), and that heregulin-induced mitogenesis involves the activation of MAPK (Marte et al, 1995). VEGF mRNA expression has been shown to be upregulated by the ras oncoprotein (Feldkamp et al, 1999;Arbiser et al, 1997;Rak et al, 1995). Additionally, inhibitors of ras function such as dominant negative ras mutants (Feldkamp et al, 1999), farnesyl-transferase inhibitors (Feldkamp et al, 1999) and lovastatin (Feleszko et al, 1999) are able to suppress VEGF production in rasoverexpressing or ras-transformed cells.…”

Section: Discussionmentioning

confidence: 95%

“…VEGF mRNA expression has been shown to be upregulated by the ras oncoprotein (Feldkamp et al, 1999;Arbiser et al, 1997;Rak et al, 1995). Additionally, inhibitors of ras function such as dominant negative ras mutants (Feldkamp et al, 1999), farnesyl-transferase inhibitors (Feldkamp et al, 1999) and lovastatin (Feleszko et al, 1999) are able to suppress VEGF production in rasoverexpressing or ras-transformed cells. Furthermore, inhibition of PI3-K (which has been shown to play an important role in erbB signaling, particularly with respect to erbB-3/erbB-2 heterodimers) led to inhibition of VEGF expression and angiogenesis (Rak et al, 2000;Arbiser et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

et al. 2000

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“…3). In particular, signalling through the Ras network is essential for both proliferation4 and angiogenesis5 of human malignant astrocytomas.…”

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confidence: 99%

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

Annibali

Whitfield

Favuzzi³

et al. 2014

Nat Commun

162

131

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Gliomas are the most common primary tumours affecting the adult central nervous system and respond poorly to standard therapy. Myc is causally implicated in most human tumours and the majority of glioblastomas have elevated Myc levels. Using the Myc dominant negative Omomyc, we previously showed that Myc inhibition is a promising strategy for cancer therapy. Here, we preclinically validate Myc inhibition as a therapeutic strategy in mouse and human glioma, using a mouse model of spontaneous multifocal invasive astrocytoma and its derived neuroprogenitors, human glioblastoma cell lines, and patient-derived tumours both in vitro and in orthotopic xenografts. Across all these experimental models we find that Myc inhibition reduces proliferation, increases apoptosis and remarkably, elicits the formation of multinucleated cells that then arrest or die by mitotic catastrophe, revealing a new role for Myc in the proficient division of glioma cells.

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Normoxic and hypoxic regulation of vascular endothelial growth factor (VEGF) by astrocytoma cells is mediated by Ras

Cited by 99 publications

References 19 publications

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis

Myc inhibition is effective against glioma and reveals a role for Myc in proficient mitosis

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