Inhibition of Epidermal Growth Factor Receptor-associated Tyrosine Kinase Blocks Glioblastoma Invasion of the Brain

Penar, Paul L.; Khoshyomn, Sami; Bhushan, Alok; Tritton, Thomas R.

doi:10.1097/00006123-199701000-00032

Cited by 78 publications

(45 citation statements)

References 67 publications

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“…Each cell line differed in ability to invade the collagen substrate, and the effects of EGFR inhibition on expression of cell adhesion molecules were variable in each carcinoma cell line. Our results support previous observations that EGFR inhibition stimulates cell-cell attachment (55) and that the EGFR is critical for invasion and metastasis of cancer cells (56,57).…”

Section: Discussionsupporting

confidence: 92%

Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Woodworth

Michael²,

Marker³

et al. 2005

Molecular Cancer Therapeutics

106

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The epidermal growth factor receptor (EGFR) is overexpressed in several types of human cancer, and inhibition of EGFR function is a promising strategy for cancer therapy. We used cDNA microarrays to examine alterations in gene expression after treatment of carcinoma cells with PD153035, a specific and reversible inhibitor of EGFR function. When human cervical carcinoma cells were grown on a collagen substrate in three-dimensional organotypic culture, untreated cells expressed high levels of EGFR RNA and invaded the underlying collagen. Blocking EGFR function decreased DNA synthesis and inhibited invasion in a dose-dependent manner. Microarray analyses identified 312 genes that were significantly increased or decreased in expression after EGFR inhibition. Many could be classified into one of four functional groups including genes that (a) stimulate inflammation and innate immunity, (b) promote cell attachment, (c) enhance apoptosis, and (d) inhibit cell cycle progression. PD153035 induced a dose-dependent activation of nuclear factor KB, a transcription factor that stimulates proinflammatory gene expression. Our results identify alterations in gene expression caused by EGFR inhibition and show that this response varies significantly in different cell lines. [Mol Cancer Ther 2005;4(4):650 -8]

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Section: Discussionsupporting

confidence: 92%

Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Woodworth

Michael²,

Marker³

et al. 2005

Molecular Cancer Therapeutics

106

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“…EGFR in the context of the human gliomas results in a strong stimulator of tumour cell migration and invasion (Lund-Johansen et al, 1990;Penar et al, 1997;Lamszus et al, 2005). Despite more investigation is needed, these evidences suggest that the blockade of the EGFR by specific mAbs may antagonise the role of the TGF-b on promote tumour cell invasion and metastasis after a radiation therapy.…”

Section: Discussionmentioning

confidence: 99%

Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies

et al. 2009

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As epidermal growth factor receptor (EGFR) has been reported to be a radiation response modulator, HER inhibitors are regarded to act as potential radiosensitisers. Our study examined the role of nimotuzumab and cetuximab both, the two monoclonal antibodies (mAbs) to EGFR, as radiosensitisers in a murine glioma model in vivo. Co-administration of both the antibodies with radiation increased the radiosensitivity of U87MG, resulting in a significant delay of subcutaneous (s.c.) tumour growth. Furthermore, the addition of antibodies to the radiation decreased brain tumour sizes and is inhibited by 40 -80% the increased tumour cell invasion provoked by radiotherapy, although promoted tumour cell apoptosis. Whereas nimotuzumab led to a reduction in the size of tumour blood vessels and proliferating cells in s.c. tumours, cetuximab had no significant antiangiogenic nor antiproliferative activity. In contrast, cetuximab induced a more marked inhibition of EGFR downstream signalling compared with nimotuzumab. Moreover, both antibodies reduced the total number of radioresistant CD133 þ cancer stem cells (CSCs). These results were encouraging, and showed the superiority of combined treatment of mAbs to EGFR and radiation over each single therapy against glioblastoma multiforme (GBM), confirming the role of these drugs as radiosensitisers in human GBM. In addition, we first showed the ability of mAb specifics against EGFR to target radioresistant glioma CSC, supporting the potential use in patients.

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“…ATP analogues of the Tyrphostin family have been developed to show specificity towards the ATP-binding sites of the EGFR and HER2 thereby inhibiting these kinases , reviewed in Levitzki 1992, Gazit et al 1991, Osherov et al 1993. The EGFR-specific AG1478 was shown to prevent primary glioblastoma cells from invading brain aggregates (Penar et al 1997) and to abrogate proliferation of prostate cancer cells (Kondapaka & Reddy 1996). In addition, AG1478 inhibits EGFR as well as HER2 signalling in MMTV/Neu+MMTV/TGFα bigenic mice and suppresses mammary tumorigenicity (Lenferink et al 2000).…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

Prenzel¹,

Fischer²,

Streit³

et al. 2001

Endocrine-Related Cancer

595

471

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Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.

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Inhibition of Epidermal Growth Factor Receptor-associated Tyrosine Kinase Blocks Glioblastoma Invasion of the Brain

Abstract: Our observations support the role of EGFR activation as a determinant by which glioblastoma invades normal brain tissue, and we show that invasion can be effectively inhibited at much lower concentrations of TK inhibitors than are necessary for growth suppression.

Cited by 78 publications

References 67 publications

Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Inhibition of the epidermal growth factor receptor increases expression of genes that stimulate inflammation, apoptosis, and cell attachment

Radiosensitisation of U87MG brain tumours by anti-epidermal growth factor receptor monoclonal antibodies

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

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