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

Abstract

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...

<p><em>Lycium barbarum</em> Polysaccharide Inhibited Hypoxia-Inducible Factor 1 in COPD Patients</p>

“…In addition, the role of HIF-1α in allergic inflammation has also been reported. 28 – 30 Here, we have reported that serum HIF-1α was significantly increased in the stable COPD patients even if average PO 2 was 66% in these patients, suggesting HIF-1α protein may be up-regulated through oxygen-independent pathway in the stable COPD patients. Furthermore, level of HIF-1α was negatively correlated with PO 2 and FEV1%, suggesting HIF-1α might be involved in the pathogenesis of COPD.…”

CMTM3 suppresses chordoma progress through EGFR/STAT3 regulated EMT and TP53 signaling pathway

“…Strong EGFR expression is significantly associated with tumor growth and metastasis [8]. Adle-Biassette demonstrated that EGFR was expressed in 244/284 (85.9%) of chordomas [46] and Yilmaz found that intensely positive EGFR was revealed in 77.5% (38/49) of chordoma patients [47]. Our previous study also found that EGFR played important roles in chordoma tumorigenesis and development [10].…”

AZD8055 enhances in vivo efficacy of afatinib in chordomas

“…Using our previously characterized chordoma PDX model (JHH‐2009‐011) [8], the anti‐tumor activities of six compounds identified in an NCGC in vitro screen with potent anti‐chordoma activity [14] were assessed in vivo . In addition, inhibitors of c‐MET and PDGFR were evaluated as these pathways are expressed and/or activated in chordomas [15–17,30]. The targets, routes of administration, and dosages tested are listed in Table 1.…”

“…In the current work, we evaluated the anti‐tumor activity of a panel of agents alone and in combination in a variety of chordoma models. More specifically, using our initial PDX model, we tested agents identified in a high‐throughput screen in the NIH Chemical Genomics Center (NCGC, now part of the National Center for Advancing Translational Sciences, NCATS) which exhibited in vitro efficacy against chordoma cell lines [14] and inhibitors of pathways known to be expressed in chordoma or shown to have benefit in a phase 2 clinical trial [15–18]. We further evaluated the anti‐tumor activity of compounds with significant in vivo efficacy in a novel chordoma PDX model established and reported here.…”