The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

Luwor, Rodney B; Lü, Yang; Li, Xinqun; Mendelsohn, John; Fan, Zhen

doi:10.1038/sj.onc.1208625

Cited by 117 publications

(99 citation statements)

References 65 publications

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“…Expression levels of HIF-1· are known to be upregulated by activation of EGFR signaling via the PI3-K/AKT and MAPK/ERK pathways (11,(17)(18)(19)40). Our results were in accord with previous studies showing that blockade of EGFR pathways by cetuximab inhibited the expression of HIF-1· in hypoxia (25,29,(41)(42)(43)(44)(45). We showed that cetuximab-mediated down-regulation of ERK1/2 and AKT phosphorylation, especially in hypoxic gastric cancer cells, led to the downstream inhibition of HIF-1·.…”

Section: Discussionsupporting

confidence: 90%

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Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines

2010

Oncol Rep

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Abstract. Hypoxia is recognized as an important factor contributing to cancer development and drug resistance. Cetuximab, a chimeric monoclonal antibody to EGFR, is known to inhibit HIF-1· expression levels and to enhance the cytotoxicity of chemotherapeutic agents. We demonstrated that hypoxia induced drug resistance in gastric cancer cells. Cetuximab enhanced oxaliplatin-induced cytotoxicity and apoptosis in normoxia and caused a reversal of drug resistance in hypoxia. Normoxic and hypoxic gastric cancer cells were treated with cetuximab, oxaliplatin or the combination and assessed for cell growth, proliferation, and apoptosis. Combination treatment resulted in a marked inhibition of HIF-1· expression levels in hypoxic cells and caused a significant reduction in the expression of activated phosphorylated AKT, ERK1/2, p-BAD and VEGF in both normoxia and hypoxia with greater levels of inhibition in hypoxia. In summary, cetuximab inhibits HIF-1· expression via the MAPK/ERK and PI3K/AKT signaling pathways and functions to overcome drug resistance induced by hypoxia. Cetuximaboxaliplatin combination therapy may therefore emerge as an attractive treatment strategy for advanced gastric cancer.

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Section: Discussionsupporting

confidence: 90%

“…Cetuximab (C225, Erbitux) is a chimeric monoclonal antibody directed to the extracellular domain of EGFR. Numerous studies have shown that cetuximab inhibited the production of vascular endothelial growth factor (VEGF) in vitro and in vivo by inhibiting HIF-1· expression levels (24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines

2010

Oncol Rep

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“…Additionally, in the present study, we observed that cetuximab partially inhibited in vivo tumor growth of the cell line that carried the mutation. It has been reported that cetuximab has the potential to inhibit angiogenesis in malignant tumors (33,34) and the potential to enhance a host's tumor immunity (35). Our results described above might reflect these actions.…”

Section: Discussionmentioning

confidence: 48%

Cetuximab inhibits the growth of mucinous ovarian carcinoma tumor cells lacking KRAS gene mutations

Sato

Saga

Mizukami³

et al. 2012

Oncol Rep

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Abstract. The purpose of this study was to explore the possibility of targeted molecular therapy with anti-epidermal growth factor receptor (anti-EGFR) antibody (cetuximab) for the treatment of mucinous ovarian carcinoma. We analyzed EGFR protein expression and KRAS gene mutations in 5 mucinous ovarian carcinoma cell lines RMUG-L, RMUG-S, MN-1, OMC-1 and MCAS and evaluated the in vitro and in vivo effects of cetuximab on each. EGFR expression was observed in all cell lines except for MN-1 cells, and a KRAS gene mutation at codon 12 was detected only in the MCAS cell line. Cetuximab inhibited RMUG-L and OMC-1 cell growth in vitro and completely blocked RMUG-L tumor growth in vivo. On the other hand, cetuximab did not affect MCAS cell growth in vitro and only partially reduced the MCAS tumor growth in vivo. These results suggest the possibility of targeted molecular therapy with cetuximab for mucinous ovarian carcinoma cells lacking a KRAS gene mutation. IntroductionOvarian cancer is the fifth leading cause of cancer-relateddeath in the United States. Ovarian cancer was reported in ~22,000 women in 2010, ~14,000 of whom ultimately died of this disease (1). Since most patients with early-stage ovarian cancer seldom have symptoms, by the time they are diagnosed, >75% are already in the advanced stage (2). The standard treatment for ovarian cancer is cytoreductive surgery with platinum/taxane combination chemotherapy. Although ovarian cancer is generally sensitive to chemotherapy (3,4), there are cases that exhibit both natively drug-resistant tumors as well as tumors that eventually acquire drug tolerance. The 5-year survival rate is only 40% and has not improved in the last decade (1). Therefore, new strategies, especially targeted molecular therapy, require more attention in order to improve the prognosis of ovarian cancer.Mucinous ovarian adenocarcinoma (MAC) accounts for 10-14% of all types of epithelial ovarian cancers (EOC) (5,6). Compared to serous adenocarcinoma (SAC), which is the most common histopathologic subgroup of EOC, MAC is relatively resistant to the conventional platinum or taxane-based chemotherapy, thereby leading to a poor prognosis (7-10). It has been reported that MAC differs from SAC pathologically and cytogenetically, and more closely resembles colorectal cancer (11). These results suggest that therapeutic agents that are effective in treating colorectal cancer may also be effective for treating MAC.Epidermal growth factor (EGF) and its receptor (EGFR) are reportedly involved in the growth and extension of malignant tumors (12). In particular, EGFR overexpression has been observed in various malignant tumors (13). Further, EGFR overexpression has been reported to be a poor prognostic factor for various malignant tumors (14,15). It has been reported that EGFR is expressed in 48% of MAC tumors, and its expression is correlated with the histologic grade, stage and death rate (16).Cetuximab, an anti-EGFR monoclonal antibody, is a molecular-targeted therapeutic agent that was produced as a human...

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“…In the same cell line, cetuximab reduced HIF-1α expression more distinctly as compared to the other epithelial cell lines in which only minor reduction of HIF-1α could be observed. Luwor et al proposed that mutations within the PTEN gene render cancer cells more resistant to cetuximab-mediated reduction of the HIF-1α level (130), which could also be of importance in our observations. Cell lines with primarily mesenchymal phenotype (LK0827 and LK0923) showed no effect of cetuximab on HIF-1α expression and only a few significant differences in treatment response between normoxia and hypoxia were found in these cell lines.…”

Section: The Impact Of Hypoxia On Hnscc Cell Linessupporting

confidence: 58%

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

Tiefenböck-Hansson¹

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v ABSTRACTSquamous cell carcinoma (SCC) is the most common histological type of cancer in the head and neck region and arises in the epithelial mucosa of the upper aerodigestive tract.Approximately one and a half million people are living with the diagnosis. Despite efforts in prevention and advances in treatment, the 5-year survival rate still lies around 60%, and recurrences and second primary tumors remain a problem. Moreover, treatment responses vary from patient to patient, highlighting the need for individually tailored treatments. To make this possible, biomarkers predicting treatment outcome are needed to better guide treatment decisions.The aim of this thesis was to evaluate the expression of certain proteins and the frequency of certain SNPs (Single nucleotide polymorphisms) in tumor biopsies and cell cultures of head and neck squamous cell carcinomas (HNSCC), and to explore their potential as biomarkers for treatment outcome. Furthermore, we aimed to study the impact of hypoxia on treatment response, epithelial-to-mesenchymal transition (EMT), and induction of cancer stem cells (CSC).In papers I and II, we investigated two proteins, survivin and WRAP53β, using immunohistochemistry (IHC) in tumor biopsies from 40 patients categorized as Nonresponders or Responders to radiotherapy. High expression of survivin and nuclear expression of WRAP53β were significantly more prevalent in the Responder group. The combination of these two factors correlated strongest to overall survival, but not to a significantly higher extent compared to survivin alone. Moreover, when examined separately, a high percentage of p53-stained cells and the presence of the SNP FGFR4 Gln388Arg correlated to improved overall survival, whereas the SNP XPD Lys751Gln was associated with worse overall survival. The latter three showed no significant correlations to radiotherapy response. In paper III, the two ABSTRACT vi most promising proteins identified in papers I and II were analyzed in a study cohort of 149 tumor biopsies of glottic laryngeal SCC, categorized as T2N0-T3N0. In this patient group, no significant associations between survivin expression and survival could be found. However, expression of cytoplasmic WRAP53β was significantly linked to worse disease-free-survival (DSF) compared to nuclear WRAP53β or negative staining for WRAP53β. Positive expression of p16INK4a was found in 7% of the tumors. The prevalence of p16 INK4a was higher in younger patients (<60) and associated with absence of recurrence and longer DSF.In paper IV, five HNSCC cell lines were cultured in normoxic (20% O 2 ) and hypoxic (1% O 2 )conditions and changes in treatment response, EMT profile, and expression of CSC markers were examined. As expected, hypoxia induced EMT and to a certain extent expression of CSC markers. Silencing of the hypoxia-inducible-factor-1α (HIF-1α) only partly reversed these effects, suggesting that other mechanisms are involved. Whereas most cell lines became more resistant to treatment in hypoxia, one cell line (LK0412) ...

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The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression

Cited by 117 publications

References 65 publications

Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines

Cetuximab enhances the effect of oxaliplatin on hypoxic gastric cancer cell lines

Cetuximab inhibits the growth of mucinous ovarian carcinoma tumor cells lacking KRAS gene mutations

The impact of Survivin, WRAP53β, and Hypoxia on treatment response in Head and Neck Cancer

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