Activated Epidermal Growth Factor Receptor in Ovarian Cancer

Hudson, Laurie G.; Zeineldin, Reema; Silberberg, Melina; Stack, M. Sharon

doi:10.1007/978-0-387-98094-2_10

Cited by 40 publications

(42 citation statements)

References 167 publications

(206 reference statements)

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“…In vitro, we found that the EGFR/NFkB signaling cascade is ligand dependent in an in vitro EOC model, which is in agreement with previous reports on EGFR activation by ligands, such as EGF, TGFa and the heparin-binding-EGF (Hudson et al, 2009) present in the EOC microenvironment. EGFR ligands can be found in the EOC microenvironment due to the activation of A disintegrin and metalloprotease by endothelin-1-or lysophosphatidic acid-stimulated Gprotein-coupled receptors (Braun and Coffey, 2005).…”

Section: Discussionsupporting

confidence: 92%

“…In a homeostatic state, EGFR has a key role in normal ovarian follicle development and cell-growth regulation of the ovarian surface epithelium (Conti et al, 2006), whose cells might give rise to EOC. In EOC tumor samples, EGFR is expressed in an estimated 10-70% of EOCs, and its altered expression is associated with advanced-stage disease and poor prognosis (Hudson et al, 2009). Very recently, EGFR overexpression has been also associated with a lack of response to chemotherapy in patients with EOC (Sheng and Liu, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

et al. 2011

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The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is expressed in up to 70% of epithelial ovarian cancers (EOCs), where it correlates with poor prognosis. The majority of EOCs are diagnosed at an advanced stage, and at least 50% present malignant ascites. High levels of IL-6 have been found in the ascites of EOC patients and correlate with shorter survival. Herein, we investigated the signaling cascade led by EGFR activation in EOC and assessed whether EGFR activation could induce an EOC microenvironment characterized by pro-inflammatory molecules. In vitro analysis of EOC cell lines revealed that ligand-stimulated EGFR activated NFkB-dependent transcription and induced secretion of IL-6 and plasminogen activator inhibitor (PAI-1). IL-6/PAI-1 expression and secretion were strongly inhibited by the tyrosine kinase inhibitor AG1478 and EGFR silencing. A significant reduction of EGF-stimulated IL-6/PAI-1 secretion was also obtained with the NFkB inhibitor dehydroxymethylepoxyquinomicin. Of 23 primary EOC tumors from advanced-stage patients with malignant ascites at surgery, 12 co-expressed membrane EGFR, IL-6 and PAI-1 by immunohistochemistry; both IL-6 and PAI-1 were present in 83% of the corresponding ascites. Analysis of a publicly available gene-expression data set from 204 EOCs confirmed a significant correlation between IL-6 and PAI-1 expression, and patients with the highest IL-6 and PAI-1 co-expression showed a significantly shorter progression-free survival time (P ¼ 0.028). This suggests that EGFR/NFkB/IL-6-PAI-1 may have a significant impact on the therapy of a particular subset of EOC, and that IL-6/PAI-1 co-expression may be a novel prognostic marker.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

et al. 2011

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“…Evidence suggests that EGFR expression may be an early event in ovarian cancer development as well as in progression and metastasis [4, 24–26]. Activated (phosphorylated) EGFR is found in 35% of primary ovarian cancers and is often elevated in peritoneal metastases relative to primary tumors from the same patient [27, 28]. A recent meta-analysis revealed a relationship between EGFR status and decreased survival [29], supporting the conclusion that aberrant EGFR status is a factor in ovarian cancer outcome.…”

Section: Introductionmentioning

confidence: 99%

Epidermal Growth Factor Receptor–Mediated Membrane Type 1 Matrix Metalloproteinase Endocytosis Regulates the Transition between Invasive versus Expansive Growth of Ovarian Carcinoma Cells in Three-Dimensional Collagen

Moss

Liu

Johnson

et al. 2009

Molecular Cancer Research

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The epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas and promotes cellular responses that contribute to ovarian cancer pathobiology. In addition to modulation of mitogenic and motogenic behavior, emerging data identify EGFR activation as a novel mechanism for rapid modification of the cell surface proteome. The transmembrane collagenase membrane type 1 matrix metalloproteinase (MT1-MMP, MMP-14) is a major contributor to pericelluar proteolysis in the ovarian carcinoma microenvironment and is subjected to extensive posttranslational regulation. In the present study, the contribution of EGFR activation to control of MT1-MMP cell surface dynamics was investigated. Unstimulated ovarian cancer cells display caveolar colocalization of EGFR and MT1-MMP, whereas EGFR activation prompts internalization via distinct endocytic pathways. EGF treatment results in phosphorylation of the MT1-MMP cytoplasmic tail, and cells expressing a tyrosine mutated form of MT1-MMP (MT1-MMP-Y 573 F) exhibit defective MT1-MMP internalization. As a result of sustained cell surface MT1-MMP activity, a phenotypic epithelial-mesenchymal transition is observed, characterized by enhanced migration and collagen invasion, whereas growth within three-dimensional collagen gels is inhibited. These data support an EGFR-dependent mechanism for regulation of the transition between invasive and expansive growth of ovarian carcinoma cells via modulation of MT1-MMP cell surface dynamics.

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“…Increased HER1 expression is an early event in ovarian cancer development, and thus may be involved in neoplasia 29 . HER1 amplification analysis in tissue microarrays showed that HER1, but not HER2, expression was greater in higher grade ovarian carcinomas 30 .…”

Section: Targets For Antibody Treatmentsmentioning

confidence: 99%

“…Depleted HER1 expression resulted in decreased E-cadherin expression by tumor cells 34 . Furthermore, overexpression of HER1 by tumor cells is associated with resistance to hormone therapies, chemotherapy and radiotherapy 29,35-37 . One proposed mechanism for this tumor cell escape is that HER1 activation leads to the up-regulation of the apoptosis inhibitor protein, survivin, which is found at high levels in many tumor types 35 …”

Section: Targets For Antibody Treatmentsmentioning

confidence: 99%

Therapeutic targets and new directions for antibodies developed for ovarian cancer

Bax

Josephs

Pellizzari

et al. 2016

mAbs

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Antibody therapeutics against different target antigens are widely used in the treatment of different malignancies including ovarian carcinomas, but this disease still requires more effective agents. Improved understanding of the biological features, signaling pathways, and immunological escape mechanisms involved in ovarian cancer has emerged in the past few years. These advances, including an appreciation of the cross-talk between cancer cells and the patient's immune system, have led to the identification of new targets. In turn, potential antibody treatments with various mechanisms of action, including immune activation or toxin-delivery, that are directed at these targets have been developed. Here, we identify established as well as novel targets for antibodies in ovarian cancer, and discuss how they may provide fresh opportunities to identify interventions with enhanced therapeutic potential.

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Activated Epidermal Growth Factor Receptor in Ovarian Cancer

Cited by 40 publications

References 167 publications

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer

Epidermal Growth Factor Receptor–Mediated Membrane Type 1 Matrix Metalloproteinase Endocytosis Regulates the Transition between Invasive versus Expansive Growth of Ovarian Carcinoma Cells in Three-Dimensional Collagen

Therapeutic targets and new directions for antibodies developed for ovarian cancer

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