Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma

Fasig, John H.; Dupont, William D.; LaFleur, Bonnie; Olson, Sandra J.; Cates, Justin M.

doi:10.1111/j.1365-2990.2007.00873.x

Cited by 41 publications

(45 citation statements)

References 38 publications

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“…Weinberger et al claim that c-erbB2 immunoreactivity is seen in 7 cases out of 11 (17) while in the study of Fasig et al no reactivity by c-erbB2 is demonstrated although two different clones of this antibody being used (16). Our results are consistent with the study of Fasig et al…”

Section: Discussionsupporting

confidence: 83%

“…In another study based on 29 cases, vertebral localization appeared to be a significant risk factor for recurrence (30). In a study by Fasig et al, no correlation was found between tumor localization and recurrence in 20 chordoma cases (16). We have not found a specific correlation between localization and recurrence in our study.…”

Section: Discussioncontrasting

confidence: 52%

“…recent studies have revealed that the molecular treatments against eGFr, erbB2 and c-met succeed in cases of lung and breast carcinomas and glioblastomas, respectively (14,15). Based on the molecular biology of chordomas, targeted therapy alternatives have been developed (16)(17)(18). However, only a few case reports are found in the literature regarding this issue.…”

mentioning

confidence: 88%

“…a study of 21 chordoma cases analysing the genes in the downstream pathways of eGFr including p44/42 MaPk, akt, stat3 has revealed that 67% of the cases were reactant by eGFr while the phosphorylated forms of p44/42 MaPk, akt, stat3 were expressed in 86%, 76%, and %67 respectively. The high expression profiles of these genes strongly indicate a role for thyrosine kinase activity in the pathogenesis of chordoma (16). Microarray studies analysing multiple genes are required to examine the exact mechanism of eGFr, cMet and c-erbB2 in chordoma.…”

Section: Discussionmentioning

confidence: 99%

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The role of egfr, hepatocyte growth factor receptor (c-met), c-erbb2 (her2-neu) and clinicopathological parameters in the pathogenesis and prognosis of chordoma

Tosuner¹,

Bozkurt²,

Kılıç³

et al. 2016

TJPATH

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InTRoDuCTIonChordoma is a rare malignant bone tumor originating from notochordal remnants (1,2). The complete resection of this tumor is usually not available because of its invasiveness to adjacent structures. although radiotherapy and gamma knife surgery have been tried for treatment, local control cannot be provided in most of the cases due to the extensive recurrence ability of the tumor (3). There are few studies investigating the effect of treatment modalities on the survival and prognosis of chordoma patients (3,4). Histopathological properties of this tumor such as mitosis and necrosis have been analysed in a number of studies in order to understand their relations with the prognosis and survival. However limited information is available from these studies and also the sample sizes are small because of the rare incidence of chordoma. There are also discordances between the results of different studies. Despite several proposed prognostic parameters, no evidence-based parameter has been defined to predict survival (5-7) receptor tyrosine kinases (rtks), besides being the key regulators of cell processes including cell growth and angiogenesis, have critical roles in the development and progression of tumors.The epidermal growth factor receptor (eGFr), erbB2 (Her-2 neu) and c-met are the members of erbB family of rtks. These trans-membrane proteins are activated by binding with peptide growth factors of the eGFfamily of proteins. eGFr and its three related proteins (the erbB family) play essential roles in both normal physiological conditions and malignancies. Upon binding its ligands, dynamic conformational changes occur in both extracellular and intracellular domains of the receptor ABsTRACTObjective: Chordoma is a rare malignant bone tumor with a poor outcome. although radiotherapy and gamma knife surgery have been used for treatment, providing a cure for the tumor is not easy, because of the frequent recurrences. Molecular targeted therapy against tyrosine kinases has been effective in the treatment of malignancies such as breast and lung cancers and brain tumors. We aimed to analyse the histopathological features of chordomas and the immunoexpression profiles of the three receptor tyrosine kinases of eGFr, c-Met and c-erb-B2 in chordomas. We have correlated these results with recurrence and overall survival status of the patients. Material and Method:We studied 49 chordoma patients in order to evaluate the histopathological features and immunohistochemical stainings by eGFr, c-Met and c-erbB2 antibodies. Of the 49 patients, follow up data was available for 40 patients. Clinical data of the patients were correlated with histopathological features and survival analysis was performed.Results: the immunostaining rate by eGFr and c-Met was 73.5% and 12.2% respectively. none of the cases showed immunoreactivity by c-erbB2 (0%). Of the 40 cases, 17 cases showed recurrences. eGFr expression was detected in 14 recurrent (14/17) and 17 non-recurrent cases (17/23). Four of the 17 recurrent cases (4/17) were posit...

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Section: Discussionsupporting

confidence: 83%

Section: Discussioncontrasting

confidence: 52%

mentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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The role of egfr, hepatocyte growth factor receptor (c-met), c-erbb2 (her2-neu) and clinicopathological parameters in the pathogenesis and prognosis of chordoma

Tosuner¹,

Bozkurt²,

Kılıç³

et al. 2016

TJPATH

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“…As it is known that chordomas also express several other tyrosine kinase receptors including c-MET, PDGFR b and KIT, EGFR, Her2/ neu and TrK, which also activate the RAS/RAF/ MEK/ERK pathway, these should be considered candidates for the regulation of brachyury. [28][29][30][31][32] The occurrence of FGFR mutations is well documented in the literature, and these are associated in both neoplasia and developmental syndromes. The mutations implicated in the former include those in endometrial, gastric, urothelial and prostatic cancers, 21,[33][34][35][36][37] and many of the activating FGFR2 and FGFR3 mutations, recently reported in endometrial carcinomas, are identical to germline mutations known to cause syndromes, several of which give rise to skeletal abnormalities including the Apert Syndrome, Beare-Stevenson Syndrome, hypochondroplasia, achondroplasia and the SAD-DAN syndrome (see Supplementary Table 2 based on Catalogue of Somatic Mutations In Cancer (COSMIC).…”

Section: Discussionmentioning

confidence: 99%

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

et al. 2009

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Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2a), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

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Methylthioadenosine phosphorylase and activated insulin‐like growth factor‐1 receptor/insulin receptor: potential therapeutic targets in chordoma

Sommer

Itani

Homlar

et al. 2010

The Journal of Pathology

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Currently there is no effective chemotherapy for chordoma. Recent studies report co-expression of insulin-like growth factor-1 receptor (IGF1R) and its cognate ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated in these tumours. Additionally, genetic studies have confirmed frequent deletions of chromosome 9p in chordomas, which encompasses the cyclin-dependent kinase inhibitor 2A (CDKN2A) locus. Another gene in this region, methylthioadenosine phosphorylase (MTAP), is an essential enzyme of the purine salvage pathway and has therapeutic relevance because MTAP-deficient cells are particularly sensitive to inhibitors of de novo purine synthesis. We investigated whether these pathways might be potential therapeutic targets for chordoma. Paraffin-embedded tissue samples from 30 chordomas were analysed by immunohistochemistry for expression of the phosphorylated isoforms of IGF1R or the insulin receptor (pIGF1R/pIR) and selected downstream signalling molecules, including BCL2-associated agonist of cell death protein (BAD). Expression of CDKN2A and MTAP proteins was also assessed. Skeletal chondrosarcomas, benign notochordal cell tumours, and fetal notochord were studied for comparison. Phosphorylated IGF1R/IR was detected in 41% of chordomas, together with activated downstream signalling molecules, and pIGF1R/pIR was absent in benign notochordal cell tumours and fetal notochord. Thirty-nine per cent of chordomas were negative for MTAP immunoreactivity. Patients with pIGF1R/pIR-positive tumours showed significantly decreased median disease-free survival in multivariate survival analysis (p = 0.036), whereas phosphorylation of BAD at serine-99 was found to be associated with a favourable prognosis (p = 0.002). Approximately 40% of chordomas demonstrate evidence of activation of the IGF1R/IR signalling pathway or loss of a key enzyme in the purine salvage pathway. Aberrant signalling cascades and disrupted metabolic pathways such as these may represent opportunities for novel targeted therapeutic approaches for the treatment of chordoma.

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Immunohistochemical analysis of receptor tyrosine kinase signal transduction activity in chordoma

Cited by 41 publications

References 38 publications

The role of egfr, hepatocyte growth factor receptor (c-met), c-erbb2 (her2-neu) and clinicopathological parameters in the pathogenesis and prognosis of chordoma

The role of egfr, hepatocyte growth factor receptor (c-met), c-erbb2 (her2-neu) and clinicopathological parameters in the pathogenesis and prognosis of chordoma

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

Methylthioadenosine phosphorylase and activated insulin‐like growth factor‐1 receptor/insulin receptor: potential therapeutic targets in chordoma

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