Cytoplasmic localization of EGF receptor in papillary thyroid carcinomas: Association with the 150-kDa receptor form

Ness, Gro Oddveig; Haugen, Dagny Faksvåg; Varhaug, Jan Erik; Akslen, Lars A.

doi:10.1002/(sici)1097-0215(19960117)65:2<161::aid-ijc6>3.0.co;2-x

Cited by 18 publications

(7 citation statements)

References 19 publications

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“…Contrary to the almost complete absence of nuclear EGFR in papillary carcinomas, cytoplasmic EGFR could easily be detected in this type of thyroid cancer in the present study. This is in agreement with other authors who have described cytoplasmic staining for the EGFR in papillary carcinomas (59)(60)(61). Akslen et al (59) even reported a correlation between cytoplasmic EGFR staining and tumor recurrence.…”

Section: Discussionsupporting

confidence: 91%

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Nuclear Localization of Epidermal Growth Factor and Epidermal Growth Factor Receptors in Human Thyroid Tissues

Marti

Ruchti

Kämpf

et al. 2001

Thyroid

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Epidermal growth factor (EGF) has widespread growth effects, and in some tissues proliferation is associated with the nuclear localization of EGF and epidermal growth factor receptor (EGFR). In the thyroid, EGF promotes growth but differs from thyrotropin (TSH) in inhibiting rather than stimulating functional parameters. We have therefore studied the occurrence and cellular distribution of EGF and EGFR in normal thyroid, in Graves' disease, where growth is mediated through the thyrotropin receptor (TSHR), and in a variety of human thyroid tumors. In the normal gland the staining was variable, but largely cytoplasmic, for both EGF and EGFR. In Graves' disease there was strong cytoplasmic staining for both EGF and EGFR, with frequent positive nuclei. Nuclear positivity for EGF and particularly for EGFR was also a feature of both follicular adenomas and follicular carcinomas. Interestingly, nuclear staining was almost absent in papillary carcinomas. These findings document for the first time the presence of nuclear EGF and EGFR in thyroid. Their predominant occurrence in tissues with increased growth (Graves' disease, follicular adenoma, and carcinoma) may indicate that nuclear EGF and EGFR play a role in growth regulation in these conditions. The absence of nuclear EGF and EGFR in papillary carcinomas would suggest that the role played by EGF in growth control differs between papillary carcinoma and follicular adenomas/carcinomas of the thyroid.

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Section: Discussionsupporting

confidence: 91%

“…Akslen et al (59) even reported a correlation between cytoplasmic EGFR staining and tumor recurrence. In addition, Ness et al (61) found that the cytoplasmic localization of the EGFR was associated with an increase of a 150-kd form of the EGFR. They speculated that this was not a defective EGFR, but presumably a partially degraded EGFR.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Localization of Epidermal Growth Factor and Epidermal Growth Factor Receptors in Human Thyroid Tissues

Marti

Ruchti

Kämpf

et al. 2001

Thyroid

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“…Although a few studies have reported EGFR degradation products after EGF treatment (42)(43)(44), to the best of our knowledge this is the first observation of these products in the plasma membrane. We have shown that addition of EGF to HeLa cells gives a decreased amount of mature receptor (170-kDa EGFR) at the plasma membrane and a relative increase in the 130-kDa protein.…”

Section: Discussionmentioning

confidence: 67%

Nanoscale Imaging of Epidermal Growth Factor Receptor Clustering

Abulrob

Baumann

et al. 2010

Journal of Biological Chemistry

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The development of some solid tumors is associated with overexpression of the epidermal growth factor receptor (EGFR) and often correlates with poor prognosis. Near field scanning optical microscopy, a technique with subdiffraction-limited optical resolution, was used to examine the influence of two inhibitors (the chimeric 225 antibody and tyrosine phosphorylation inhibitor AG1478) on the nanoscale clustering of EGFR in HeLa cells. The EGFR is organized in small clusters, average diameter of 150 nm, on the plasma membrane for both control and EGF-treated cells. The numbers of receptors in individual clusters vary from as few as one or two proteins to greater than 100. Both inhibitors yield an increased cluster density and an increase in the fraction of clusters with smaller diameters and fewer receptors. Exposure to AG1478 also decreases the fraction of EGFR that colocalizes with both rafts and caveolae. EGF stimulation results in a significant loss of the full-length EGFR from the plasma membrane with the concomitant appearance of low molecular mass proteolytic products. By contrast, AG1478 reduces the level of EGFR degradation. Changes in receptor clustering provide one mechanism for regulating EGFR signaling and are relevant to the design of strategies for therapeutic interventions based on modulating EGFR signaling.The plasma membrane of the cell is a complex, carefully regulated, dynamic structure that is compartmentalized into cell surface domains such as lipid rafts, caveolae, and clathrincoated pits (1). Lipid rafts are postulated to be dynamic nanodomains ranging in size from 10 to 200 nm that are enriched in cholesterol, sphingolipids, and certain proteins and that play an important role in assembling signaling complexes (2-4). Caveolae are invaginated lipid raft domains (50 -150 nm) whose stability at the plasma membrane is attributable to the formation of stable oligomers of their coat protein, caveolin-1 (5). Caveolae are thought to serve as concentrators of various signal transduction machineries. Clathrin-coated pits (100 -150 nm) internalize rapidly upon formation at the plasma membrane, and their lateral cell surface mobility is enhanced by actin cytoskeleton depolymerization (6).The epidermal growth factor receptor (EGFR), 3 a 170-kDa transmembrane glycoprotein, is one of four members of the ErbB family of receptor tyrosine kinases involved in oncogene signaling. The initial step in receptor activation involves binding of the EGF peptide to the extracellular domain leading to dimerization or activation of pre-existing dimers (7,8). Following ligand binding, the EGFR is auto-phosphorylated in several tyrosine residues of the intracellular domain, creating high affinity sites for various adaptor molecules that transmit the mitogenic signal to the Ras/MAPK signal transduction pathway (9). Activation of Ras initiates a multistep phosphorylation cascade that leads to the activation of MAPKs, ERK1, and ERK2, which regulate transcription of molecules that are linked to cell proliferation, survival, a...

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“…In breast tumours, membrane staining of the c-erbB-2/neu has been suggested to be associated with c-erbB-2/neu ampli®cation [48]. Cytoplasmic staining of c-erbB-2/neu has been reported [46,49], but its interpretation has been controversial. However, ®ndings of mixed cytoplasmic/ membrane staining were suggested to identify the c-erbB-2/neu [46].…”

Section: Discussionmentioning

confidence: 99%

“…Cytoplasmic staining of c-erbB-2/neu has been reported [46,49], but its interpretation has been controversial. However, ®ndings of mixed cytoplasmic/ membrane staining were suggested to identify the c-erbB-2/neu [46]. In line with that, we found mixed cytoplasmic/membrane staining in 14 out of the 24 carcinomas investigated, and the staining was blocked using the speci®c blocking peptides.…”

Section: Discussionmentioning

confidence: 99%

Expression of biomarkers (p53, transforming growth factor alpha, epidermal growth factor receptor, c-erbB-2/neu and the proliferative cell nuclear antigen) in oropharyngeal squamous cell carcinomas

et al. 1999

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Using immunohistochemistry, expression of p53, transforming growth factor-alpha (TGF-a), epidermal growth factor receptor (EGFR), c-erbB-2/neu and proliferating cell nuclear antigen (PCNA) was examined in 26 fresh frozen tissue specimens of oropharyngeal squamous cell carcinomas (SCCs). p53 gene mutations were examined by polymerase chain reaction (PCR)/DNA sequencing methods in 22 carcinomas. The ®ndings were examined for correlations with patients' clinicopathological parameters. Expressions of p53 and PCNA were also examined in 21 formalin-®xed corresponding tissues. Of the fresh frozen tissue specimens, 77% (20/26) showed expression and 68% (15/22) showed mutations (substitutions) of the p53, with signi®cant clustering of the mutations in exons 5 (8/22; 36%), 7 (4/22; 18%) and 8 (5/22; 23%). No mutations were found in exon 6. There was a discordance between expression of p53 protein and mutations of the gene. Parallel to expression and mutations of the p53 found in most of the specimens, expression of TGF-a, EGFR, c-erbB-2/neu and PCNA was found in 88% (22/25), 92% (23/25), 58% (14/24) and 91% (21/23) of the specimens, respectively. For the formalin-®xed tissue specimens, 62% (13/21) and 90% (19/21) expressed p53 and PCNA, respectively. Examining for correlations with patients' clinicopathological parameters, expression of p53, TGF-a, EGFR and c-erbB-2/neu seemed to negatively correlate with the increase of the tumour grade. The present work suggests that: (1) lack of negative growth regulation due to inactivation of the p53 gene together with activation of other proto-oncogenes are necessary genetic events in the carcinogenesis of oropharyngeal SCCs; (2) in oropharyngeal SCCs, p53 gene mutations were clustered in exons 5 (codons 130±186), 7 (codons 230±248) and 8 (codons 271±282) which perhaps suggests that tobacco carcinogens probably aect the mutational hot spots of the p53 gene at codons 157, 175, 186, 248, 273 and 282; and (3) fresh frozen and formalin-®xed tissue specimens give similar results when an immunohistochemical method is applied. The importance of p53, TGF-a, EGFR, c-erbB-2/ neu and PCNA as biomarkers in oropharyngeal SCCs deserves particular attention because it might oer further understanding of the development of these carcinomas. #

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Cytoplasmic localization of EGF receptor in papillary thyroid carcinomas: Association with the 150-kDa receptor form

Cited by 18 publications

References 19 publications

Nuclear Localization of Epidermal Growth Factor and Epidermal Growth Factor Receptors in Human Thyroid Tissues

Nuclear Localization of Epidermal Growth Factor and Epidermal Growth Factor Receptors in Human Thyroid Tissues

Nanoscale Imaging of Epidermal Growth Factor Receptor Clustering

Expression of biomarkers (p53, transforming growth factor alpha, epidermal growth factor receptor, c-erbB-2/neu and the proliferative cell nuclear antigen) in oropharyngeal squamous cell carcinomas

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