Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop

Guha, Abhijit; Dashner, Kathleen; Black, Peter L. Mc; Wagner, John A.; Stiles, Charles D.

doi:10.1002/ijc.2910600206

Cited by 258 publications

(140 citation statements)

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“…It is consistent with the previous findings that malignant gliomas (anaplastic astrocytomas and the most malignant type, glioblastoma multiforme) overexpress the ligands PDGF-A and -B compared to low-grade gliomas or normal tissues (Maxwell et al, 1990;Hermanson et al, 1992;Guha et al, 1995). Moreover, the retrovirus-mediated expression of PDGF-B in the brain of neonatal mice results in the formation of astrocytomas (Uhrbom et al, 1998).…”

Section: Discussionsupporting

confidence: 90%

“…Bar, 10 mm. 1992; Smits et al, 1992;Vassbotn et al, 1993;Guha et al, 1995). Secreted PDGF binds to extracellular domain of cell surface PDGFR, resulting in receptor dimerisation.…”

Section: Discussionmentioning

confidence: 99%

“…One of the important factors that consist of this phenomenon is the autocrine signalling of growth factors (Vassbotn et al, 1993). The coexpression of platelet-derived growth factor (PDGF) and its receptor (PDGFR) is frequently detected in a variety of tumours including malignant glioma (Maxwell et al, 1990;Hermanson et al, 1992;Guha et al, 1995), lung cancer (Antoniades et al, 1992), and sarcoma (Smits et al, 1992), suggesting the existence of PDGF autocrine loop. Platelet-derived growth factor, a potent mitogen for glial cells, vascular smooth muscle cells, and fibroblasts, exists as disulphide-linked dimers of four homologous polypeptide chains, PDGF-A and -B, and the recently identified PDGF-C and PDGF-D (Ross et al, 1986;Deuel, 1987;Li et al, 2000;Bergsten et al, 2001;Gilbertson et al, 2001;LaRochelle et al, 2001).…”

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Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

et al. 2004

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Malignant gliomas highly coexpress platelet-derived growth factor (PDGF) and its receptor, suggesting the presence of an autocrine loop. Therefore, disruption of PDGF ligand/receptor complex represents a promising strategy for the treatment of malignant gliomas. However, the mechanisms of the antitumour effect exerted by the inhibition of PDGF-mediated cell growth remain unclear. In the present study, using anti-PDGF neutralising antibody, we investigated the effect of the inhibition of PDGF signalling on malignant glioma U87-MG, D54, and T98G cells with high levels of PDGF-A and -B. As a control, normal fibroblast MRC5 cells expressing low levels of PDGF-A and -B were used. Treatment with anti-PDGF neutralising antibody did not affect the expressions of PDGF-A, PDGF-B, and Akt, but suppressed the level of phosphorylated Akt in tumour cells, indicating the inhibition of PDGF signalling. The cell viability of all malignant glioma cells tested in this study was significantly inhibited in a time-dependent manner following the treatment compared to that of fibroblast cells (Po0.02 to o0.05). The antitumour effect of anti-PDGF antibody was suppressed by the activation of Akt and enhanced by the downregulation of Akt. Interestingly, the inhibition of PDGF signalling induced the development of acidic vesicular organelles and the autophagosome membrane association of the microtubule-associated protein light chain 3, which are characteristic of autophagy, in malignant glioma cells, while apoptotic cell death was not observed. Together these findings imply a new concept of autophagy for PDGF autocrine inhibition in malignant gliomas.

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Section: Discussionsupporting

confidence: 90%

“…Bar, 10 mm. 1992; Smits et al, 1992;Vassbotn et al, 1993;Guha et al, 1995). Secreted PDGF binds to extracellular domain of cell surface PDGFR, resulting in receptor dimerisation.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

et al. 2004

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“…Oncogenic Ras mutations have not been discovered in human astrocytomas (Bos, 1989;Tuzi et al, 1991), which constitute the most common primary malignancy involving the central nervous system (Zimmerman, 1969). However, it has been demonstrated that high grade (grade IV) astrocytomas, known as glioblastoma multiforme (GBM), express high levels of ligand-dependent and -independent growth factor receptors (Fleming et al, 1992;Guha et al, 1995a;Libermann et al, 1984;NisteÂ r et al, 1988;Steck et al, 1988;Sugawa et al, 1990;Wong et al, 1992) which are functionally relevant for tumour growth (Guha et al, 1995a,b;Shamah et al, 1993). We have demonstrated these various receptors to result in a functional activation of the Ras pathway in a wide range of astrocytoma cell lines (U87, U118, U138, U343 and U373-MG cells).…”

Section: Introductionmentioning

confidence: 99%

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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“…First, gliomas frequently overexpress PDGF and PDGFRs in an autocrine/paracrine manner (Nister et al, 1988;Hermanson et al, 1992;Guha et al, 1995;Lokker et al, 2002). Second, c-KIT is expressed by many GBM tumours (Went et al, 2004;Joensuu et al, 2005).…”

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confidence: 99%

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Dresemann²,

et al. 2009

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We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSION: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

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Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop

Cited by 258 publications

References 14 publications

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

Inhibition of platelet-derived growth factor signalling induces autophagy in malignant glioma cells

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

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

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