Expression of Epidermal Growth Factor Receptor and HER-2 in Pediatric Embryonal Brain Tumors

Patereli, Amalia; Alexiou, George Α.; Stefanaki, Kalliopi; Moschovi, Maria; Doussis-Anagnostopoulou, Ipatia; Prodromou, Neofytos; Karentzou, Ourania

doi:10.1159/000316640

Cited by 18 publications

(9 citation statements)

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“…5b ). Though expression data from MRT and AT/RT tumors and cell lines suggests overexpression of ErbB2/Her2 relative to other central nervous system tumors [ 30 , 31 ], in our system we detect no Smarcb1 dependent change in the expression of ErbB2. ErbB4, as in most cases [ 32 ], is not expressed and unresponsive to Smarcb1 .…”

Section: Resultscontrasting

confidence: 74%

“…6 ). Several studies in human Rhabdoid tumor cells have demonstrated Lapatinib and Gefitinib as highly effective in inhibition of proliferation, consistent with high levels of EGFR / ErbB expression and signaling [ 30 , 45 , 46 ]. Taken together, our results reproduce these findings and reinforce the possibility of targeted EGFR/ErbB therapy in MRT and AT/RT patients.…”

Section: Discussionmentioning

confidence: 94%

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Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in Malignant Rhabdoid tumor cells

et al. 2015

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BackgroundThe SWI/SNF ATP dependent chromatin remodeling complex is a multi-subunit complex, conserved in eukaryotic evolution that facilitates nucleosomal re-positioning relative to the DNA sequence. In recent years the SWI/SNF complex has emerged to play a role in cancer development as various sub-units of the complex are found to be mutated in a variety of tumors. One core-subunit of the complex, which has been well established as a tumor suppressor gene is SMARCB1 (SNF5/INI1/BAF47). Mutation and inactivation of SMARCB1 have been identified as the underlying mechanism leading to Malignant Rhabdoid Tumors (MRT) and Atypical Teratoid/Rhabdoid Tumors (AT/RT), two highly aggressive forms of pediatric neoplasms.MethodsWe present a phosphoproteomic study of Smarcb1 dependent changes in signaling networks. The SILAC (Stable Isotopic Labeling of Amino Acids in Cell Culture) protocol was used to quantify in an unbiased manner any changes in the phosphoproteomic profile of Smarcb1 deficient murine rhabdoid tumor cell lines following Smarcb1 stable re-expression and under different serum conditions.ResultsThis study illustrates broad changes in the regulation of multiple biological networks including cell cycle progression, chromatin remodeling, cytoskeletal regulation and focal adhesion. Specifically, we identify Smarcb1 dependent changes in phosphorylation and expression of the EGF receptor, demonstrate downstream signaling and show that inhibition of EGFR signaling specifically hinders the proliferation of Smarcb1 deficient cells.ConclusionsThese results support recent findings regarding the effectivity of EGFR inhibitors in hindering the proliferation of human MRT cells and demonstrate that activation of EGFR signaling in Rhabdoid tumors is SMARCB1 dependent.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0439-5) contains supplementary material, which is available to authorized users.

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Section: Resultscontrasting

confidence: 74%

Section: Discussionmentioning

confidence: 94%

Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in Malignant Rhabdoid tumor cells

et al. 2015

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“…Nam et al [25] and Meurer et al [26] found a significant correlation of MIB-1 index with patients survival. Likewise, in a previous study we found that a Ki-67 index over 50% was associated with a worse overall survival [27]. …”

Section: Discussionsupporting

confidence: 52%

Prognostic Significance of Angiogenesis in Relation to Ki-67, p-53, p-27, and bcl-2 Expression in Embryonal Tumors

Moschovi

Koultouki

Stefanaki³

et al. 2011

Pediatr Neurosurg

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Aim: We investigated the angiogenesis and density of newly formed blood vessels in embryonal tumors in relation to Ki-67, bcl-2, p-53 and p-27 expression. Methods: Forty-five children with embryonal tumors were enrolled in the study. Forty patients had a medulloblastoma (MB) and 5 patients had atypical teratoid/rhabdoid tumor (AT/RT). Results: In MB, the 5-year PFS and OS was 62.5 and 70%, respectively. Patients with Ki-67 index >50%, bcl-2 index >30% and higher density of new vessels were associated with worse survival. In the multivariate analysis, Ki-67 index was identified as a factor with independent prognostic power. In AT/RTs, high density of new vessels (>25 HRF) was observed in 3 patients and Ki-67 index over 25% was found in 4 patients. Conclusion: Increased Ki-67, bcl-2 and density of new vessels are of prognostic value for the disease outcome in MB.

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“…Aberrant growth factor receptor expression and activity has been shown to be important in the pathogenesis of a variety of malignancies, and a variety of growth factors and GFRs are aberrantly expressed in pediatric cancer cells and tumors (Goumnerova 1996;Abella and Park 2009), including the neurotrophin receptors TrkA, TrkB, and TrkC (Thiele et al, 2009); fibroblast growth factor receptors (Janet et al, 1995;Duplan et al, 2002;Goldstein et al, 2007), platelet-derived growth factor receptors (PDGFR) (Matsui et al, 1993;Östman and Heldin, 2007;Thorarinsdottir et al, 2008;Shimada et al, 2008), vascular endothelial growth factor receptors(VEGFR) (Meister et al, 1999;Langer et al, 2000, Fakhari et al, 2002Nowicki et al, 2007;Slongo et al, 2007), c-kit (Shimada et al, 2008;Blom et al, 2010;Puputti et al, 2010), RET (Hishiki et al, 1998), c-Met (Hecht et al, 2004;Li et al, 2005;Diomedi-Camassei et al, 2008), and the ErbB receptor family (EGFR, her-2, her-3, her-4) (Bredel et al, 1999;Bodey et al, 2005;Vasei et al, 2009;Patereli et al, 2010;Izycka-Swieszewska et al, 2011). However, the mechanisms responsible for the regulation of GFR expression in pediatric cancer cells are not well understood.…”

Section: Introductionmentioning

confidence: 99%

Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer

Zage

Bean

2012

Front. Biol.

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Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and altered GFR expression and activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intracellular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments.The intracellular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies.The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis. c-Cbl ubiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitination and trafficking and leukemogenesis. We have shown that UBE4B plays a crucial role in GFR trafficking and degradation in tumor cells, suggesting a previously uncharacterized link between UBE4B and tumorigenesis. With the critical need for new and effective therapies for pediatric malignancies, the recently identified roles for the GFR trafficking pathway in the pathogenesis of various forms of cancer confirm the importance of the further development of novel therapies targeting this pathway in children with cancer.

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Expression of Epidermal Growth Factor Receptor and HER-2 in Pediatric Embryonal Brain Tumors

Cited by 18 publications

References 29 publications

Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in Malignant Rhabdoid tumor cells

Phosphoproteomic analysis reveals Smarcb1 dependent EGFR signaling in Malignant Rhabdoid tumor cells

Prognostic Significance of Angiogenesis in Relation to Ki-67, p-53, p-27, and bcl-2 Expression in Embryonal Tumors

Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer

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