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

Prenzel, Norbert; Fischer, Oliver M.; Streit, Sylvia; Hart, Stefan; Ullrich, Axel

doi:10.1677/erc.0.0080011

Cited by 595 publications

(498 citation statements)

References 212 publications

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“…EGFR expression has often been linked with cell proliferation (14)(15)(16). Therefore, we studied the impact of EGFR inhibition on DU145 and PC-3 cell proliferative capacity.…”

Section: Aee788 Leads To Increased Inhibition Of Cell Proliferation Imentioning

confidence: 99%

“…Furthermore, in pre-clinical studies involving various cancer models, including prostate tumors, EGFR overexpression has been linked to proliferation, angiogenesis, and migration (14)(15)(16), and has an inverse relationship to tumor radiocurability (17,18). In prostate cancer, EGFR expression correlates with higher Gleason score, higher PSA values, and is an independent prognostic factor negatively impacting disease free survival (19).…”

Section: Introductionmentioning

confidence: 99%

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Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Huamani

Willey

Thotala

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To determine the efficacy of combining radiation (XRT) with a dual EGFR/VEGFR inhibitor, AEE788, in prostate cancer models with different levels of EGFR expression. Methods and Materials-Immunoblotting was performed for EGFR, phosphorylated-EGFR (p-EGFR), and p-AKT in prostate cancer cells. Clonogenic assays were performed on DU145, PC-3 and HUVEC cells treated with XRT+/−AEE788. Tumor xenografts were established for DU145 and PC-3 on hindlimbs of athymic nude mice assigned to four treatment groups: 1) Control, 2) AEE788, 3) XRT, 4) AEE788+XRT. Tumor blood flow and growth measurements were performed using immunohistochemistry and imaging.Results-AEE788 effectively reduced p-EGFR and p-AKT levels in DU145 and PC-3 cells. Clonogenic assays showed no radiosensitization for DU145 and PC-3 colonies treated with AEE788 +XRT. However, AEE788 caused decreased proliferation in DU145 cells. AEE788 showed radiosensitization effect in HUVEC and increased apoptotis susceptibility. Concurrent AEE788 +XRT compared to either alone led to significant tumor growth delay in DU145 tumors. In contrast, PC-3 tumors derived no added benefit to combined modality therapy. In the DU145 tumors, significant reduction in tumor blood flow with combination therapy was demonstrated by power Doppler sonography and tumor blood vessel destruction on immunohistochemistry. MS imaging demonstrated that AEE788 is bioavailable and heterogeneously distributed in DU145 tumors undergoing therapy. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conclusion-AEE788+XRT showed efficacy in vitro/in vivo with DU145-based cell models while PC-3-based were adequately treated with radiation alone without added benefit from combination therapy. These findings correlated with differences in EGFR expression and demonstrated effects on both tumor cell proliferation and vascular destruction. NIH Public Access

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“…EGFR expression has often been linked with cell proliferation (14)(15)(16). Therefore, we studied the impact of EGFR inhibition on DU145 and PC-3 cell proliferative capacity.…”

Section: Aee788 Leads To Increased Inhibition Of Cell Proliferation Imentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Huamani

Willey

Thotala

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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“…Cisplatin activates nuclear as well as cytoplasmatic signalling pathways involved in regulation of the cell cycle, damage repair and programmed cell death and it also activates a membraneintegrated protein, the epidermal growth factor receptor (EGFR) [4]. EGFR, commonly expressed in a variety of human tumours, thyroid cancer included [5], provides a target for cancer therapy since EGFR-tyrosine kinase inhibitors caused growth inhibition of tumours and enhancement of the activity of a number of cytotoxic drugs [6,7]. In response to cisplatin, EGFR has been implicated in the activation of downstream events [8], including extracellular signal-regulated kinase (ERK) [4].…”

Section: Introductionmentioning

confidence: 99%

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

Muscella

Urso

Calabriso

et al. 2009

Biochemical Pharmacology

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“…16,17 Increased expression of EGFR and its ligands in HNSCC has been associated with a poorer prognosis 18 and been shown to promote malignant transformation and tumorigenesis in vitro and in vivo. 19 -21 EGFR has been reported to modulate several important mechanisms involved in tumor development, progression and therapeutic resistance, including angiogenesis.…”

mentioning

confidence: 99%

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

220

190

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Key words: EGFR; NF-B; AP-1; IL-8; VEGF; PI3K; MEK; HNSCCIncreased angiogenesis is critical to tumor progression and metastasis, and we and others have shown that expression of members of the C-X-C cytokine and vascular endothelial growth factor families such as IL-8, growth regulated oncogene-1 (Gro 1) and VEGF can promote angiogenesis, tumorigenesis and metastatic tumor progression. 1-3 The expression of multiple factors with proangiogenic activity by cancer cells poses a significant obstacle to effective therapy with agents targeted toward individual factors and receptors. Identification of common mechanism(s) underlying expression of such a diversity of factors could guide the development of therapy using fewer selective agents. We previously observed that IL-8, VEGF and other cytokines are coexpressed and often vary concurrently in serum and supernatants from cell lines from different patients with head and neck squamous cell carcinoma (HNSCC), 4,5 suggesting that these factors could be regulated by common signal pathways or transcription factors.Examination of the regulatory region of many proinflammatory cytokines and proangiogenic factors reveals that they share common promoter sites for transcription factors such as nuclear factor-B (NF-B) and/or activator protein-1 (AP-1), which can be activated by injury, cytokines and growth factors. 6 We found that differences in expression of these cytokines in different cancers was often related to differences in constitutive activation of both NF-B and AP-1. 6 Inhibition of NF-B activation by expression of a dominant negative inhibitor-B or pharmacologic agents was found to inhibit expression of IL-8 and other proinflammatory and proangiogenic cytokines, 7-10 as well as tumorigenesis and angiogenesis in vivo. 7,9 Inhibition of activation of extracellular signalregulated kinase (ERK) and AP-1 with antagonists of mitogenactivated/extracellular signal-regulated kinase (MEK) partially inhibited expression of both IL-8 and VEGF. 10 These results provided evidence that at least 2 signal pathways upstream of NF-B and AP-1 make important contributions to expression of these angiogenesis factors.We have recently examined the contribution of several factors that may contribute to upstream signal activation of NF-B and AP-1 and expression of IL-8 and VEGF. We found that IL-1␣ expressed by HNSCC promotes autocrine activation of NF-B and AP-1, expression of IL-8 and cell survival. 11 Expression of IL-1 receptor antagonist inhibited NF-B reporter activity and IL-8 expression by 60 -80%, indicating that IL-1␣ is a major contributor to constitutive activation of NF-B and IL-8. HNSCC were also found to express c-MET, a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). 12 Increased expression of HGF/SF was detected together with IL-8 and VEGF in serum of patients with HNSCC, and recombinant HGF and HGF from stromal fibroblasts was found to further induce IL-8 and VEGF expression by human HNSCC lines. Inhibitors of MEK and Abbreviations: AP-1, activator...

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

Cited by 595 publications

References 212 publications

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Differential Efficacy of Combined Therapy With Radiation and AEE788 in High and Low EGFR-Expressing Androgen-Independent Prostate Tumor Models

Functions of epidermal growth factor receptor in cisplatin response of thyroid cells

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

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