The Growth-Response of Human Tumor-Cell Lines Expressing the Egf Receptor to Treatment With Egf and or Mabs That Block Ligand-Binding

Modjtahedi, Helmout; Styles, J M; Dean, Christopher

doi:10.3892/ijo.3.2.237

Cited by 7 publications

(9 citation statements)

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“…3D). It has already been reported that EGF inhibits the growth of HN5 cells and can induce senescence [45]. We confirmed the inhibitory effect of EGF on wild-type HN5 cells by MTT assay; however, ANXA1 knockdown HN5 cells had the tendency to show increased survival in the presence of 5 and 50 ng/ml recombinant EGF (Fig.…”

Section: Anxa1 Regulates Egfr Signallingsupporting

confidence: 72%

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Raulf

Lucarelli

Thavaraj

et al. 2018

European Journal of Cancer

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Background: Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer with approximately half a million cases diagnosed each year worldwide. HNSCC has a poor survival rate which has not improved for over 30 years. The molecular pathogenesis of HNSCCs remains largely unresolved; there is high prevalence of p53 mutations and EGFR overexpression; however, the contribution of these molecular changes to disease development and/or progression remains unknown. We have recently identified microRNA miR-196a to be highly overexpressed in HNSCC with poor prognosis. Oncogenic miR-196a directly targets Annexin A1 (ANXA1). Although increased ANXA1 expression levels have been associated with breast cancer development, its role in HNSCC is debatable and its functional contribution to HNSCC development remains unclear. Methods: ANXA1 mRNA and protein expression levels were determined by RNA Seq analysis and immunohistochemistry, respectively. Gain-and loss-of-function studies were performed to analyse the effects of ANXA1 modulation on cell proliferation, mechanism of

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Section: Anxa1 Regulates Egfr Signallingsupporting

confidence: 72%

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Raulf

Lucarelli

Thavaraj

et al. 2018

European Journal of Cancer

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“…237 The greater impact of EGF on the cetuximab treatment response could be explained by the fact that EGF has a much higher affinity to EGFR than AR and EPR. 238,239 Interestingly, stromal cells were shown to have a higher expression of EGF than epithelial cells.…”

Section: Discussion Paper IImentioning

confidence: 99%

Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer

Ansell¹

2013

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V ABSTRACTHead and neck squamous cell carcinoma (HNSCC) poses a major health problem in the world with approximately 600 000 new cases yearly. Treatment resistance is a major problem within this patient group and despite advances in treatment strategies the overall survival rate has unfortunately not increased.One of the major components of the tumor microenvironment is the cancer associated fibroblasts (CAFs) which can modulate the treatment sensitivity, tumor growth, and the invasive potential of tumor cells.The aim of this thesis was to identify predictive markers for treatment response in HNSCC and to study the crosstalk between tumor cells and CAFs that may underlie treatment resistance.In paper I, we identified gene expression differences between one cisplatin sensitive cell line and two cisplatin resistant cell lines, by microarray analysis, and found that a high expression of matrix metalloproteinase (MMP) -7 was associated with resistance to cisplatin. In paper II, the epidermal growth factor (EGF) receptor ligands EGF, amphiregulin, and epiregulin were evaluated regarding their potential use as predictive biomarkers for cetuximab treatment response in tongue cancer cell lines and it was shown that EGF may serve as a marker for poor cetuximab response. In paper III and IV, we investigated the influence of CAFs on the proliferation, migration, gene expression, and cetuximab response of tumor cells. It was found that CAFs induced resistance to cetuximab in a MMP-dependent manner. In addition, a microarray analysis, ABSTRACT VI comparing tumor cells co-cultured with CAFs and tumor cells cultured alone, revealed that CAFs induced multiple gene expression changes in tumor cells some of which are related to epithelial to mesenchymal transition. Some of these changes were found to be dependent on cell-cell contact.Taken together, we here suggest MMP-7 and EGF to be predictive markers of cisplatin and cetuximab response, respectively. We also show that CAFs protect HNSCC cells from cetuximab treatment; however, the factor responsible for the protective effect is yet to be discovered.

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“…This effect could not be achieved after downregulation of EREG. This EGFR expression-dependent pattern of response to ligands has been previously described (Modjtahedi et al 1993;O-charoenrat et al 2000). Earlier studies suggested that cell lines with high EGFR expression are sensitive to very low ligand concentrations while growth inhibition occurs at higher concentrations (Modjtahedi et al 1993).…”

Section: Cetuximab Resistancementioning

confidence: 99%

“…This EGFR expression-dependent pattern of response to ligands has been previously described (Modjtahedi et al 1993;O-charoenrat et al 2000). Earlier studies suggested that cell lines with high EGFR expression are sensitive to very low ligand concentrations while growth inhibition occurs at higher concentrations (Modjtahedi et al 1993). We therefore propose in paper III based on these findings that the level of EGF under basal conditions was within the concentration range optimal for growth stimulation for all three cell lines.…”

Section: Cetuximab Resistancementioning

confidence: 99%

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Understanding the Role of EGFR in the Treatment of Head and Neck Squamous Cell Carcinoma

Jedliński¹

2014

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Head and neck squamous cell carcinoma (HNSCC) originates from the epithelial lining of the upper aerodigestive tract. It accounts for over 90 % of the malignancies found in the head and neck region. 600,000 new cases of HNSCC occur each year worldwide. Apart from causing painful lesions, HNSCC directly impacts the patient’s fundamental functions such as breathing and eating and also can disrupt the patient’s senses such as smell, taste, speech and even vision. Most cases of HNSCC require a combination of different treatments such as surgery, chemotherapy (primarily cisplatin based), and radiotherapy. Treatment decisions are largely based on the size of the tumor, the involvement of local lymph nodes, and distant spread. Treatment resistance and local recurrence are significant problems and to date no form of clinical treatment sensitivity prediction is available. A majority of HNSCC tumors overexpresses the epidermal growth factor receptor (EGFR). This receptor is involved in proliferation and DNA repair and is the target of a monoclonal antibody named cetuximab that selectively binds and inhibits EGFR. It is the only targeted therapy available to HNSCC patients and reserved for late stage patients in Sweden. Numerous investigators have searched for predictive markers and we hypothesized that since HNSCC is a very heterogeneous disease a single factor would not be able to predict the treatment outcome. In paper I we explore a panel of predictive factors using a point system, called the number of negative points (NNP), in which we could combine both proteins and genetic variations in an attempt to find a set of markers that could predict the intrinsic cisplatin sensitivity (ICS). The expression level of EGFR, Hsp70, Bax, Bcl-XL, survivin, and COX-2 was determined in 39 HNSCC cell lines. Moreover, the p53, MDM2, FGFR4, XPC, XPD, XRCC1, and XRCC3 genes were analyzed for the presence of specific single nucleotide polymorphisms (SNPs). Pearson’s correlation tests showed that EGFR was the only protein that alone correlated to ICS (r=0.388, P=0.015). The strongest correlation to ICS was found when combining SNPs in XRCC3 and XPD with the expression of EGFR, Hsp70, Bax, and Bcl-2 using the NNP system (r=0.614 P≤0.001). In paper II we assess the intrinsic radiosensitivity (IR), the ICS, and the intrinsic cetuximab sensitivity (ICmabS) as well as their combinations in 25 HNSCC cell lines established from HNSCC biopsies taken at the Department of Otorhinolaryngology and Head and Neck Surgery at Linköping University Hospital. Furthermore we investigate the EGFR status (consisting of EGFR gene copy number, EGFR mRNA, EGFR protein, pEGFR), pAkt and mRNA levels of the seven known EGFR ligands. No correlation was found between the different treatment sensitivities. Cetuximab treatment response was significantly correlated to epiregulin (EREG) mRNA expression (r=-0.408, P=0.043). Cetuximab resistant cell lines tended to have low levels of pEGFR (P=0.13) while resistant cell lines had a significantly lower expression of EGFR pro...

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The Growth-Response of Human Tumor-Cell Lines Expressing the Egf Receptor to Treatment With Egf and or Mabs That Block Ligand-Binding

Cited by 7 publications

References 0 publications

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers

Identification of Tumor Cell- and Stroma Derived Biomarkers of Treatment Response in Head and Neck Cancer

Understanding the Role of EGFR in the Treatment of Head and Neck Squamous Cell Carcinoma

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