Levels of TGF-α and EGFR Protein in Head and Neck Squamous Cell Carcinoma and Patient Survival

Grandis, Jennifer R.; Melhem, Mona F.; Gooding, William E.; Day, Roger; Holst, Valerie A.; Wagener, Marilyn M.; Drenning, Stephanie D.; Tweardy, David J.

doi:10.1093/jnci/90.11.824

Cited by 994 publications

(667 citation statements)

References 43 publications

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“…These data provide evidence for a link between EGFR activation, 18 coactivation of NF-B and AP-1 6 and coexpression of IL-8 and VEGF 5,10 in HNSCC. Our data indicate that inhibition of NF-B and AP-1 activation and proangiogenic factor expression may be an important mechanism underlying the activity of anti-EGFR antibodies and tyrosine kinase inhibitors in HNSCC and other cancers that overexpress EGFR.…”

Section: Discussionmentioning

confidence: 57%

“…16,17 Increased expression of EGFR and its ligands in HNSCC has been associated with a poorer prognosis 18 and been shown to promote malignant transformation and tumorigenesis in vitro and in vivo. 19 -21 EGFR has been reported to modulate several important mechanisms involved in tumor development, progression and therapeutic resistance, including angiogenesis.…”

mentioning

confidence: 99%

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Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

220

190

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Key words: EGFR; NF-B; AP-1; IL-8; VEGF; PI3K; MEK; HNSCCIncreased angiogenesis is critical to tumor progression and metastasis, and we and others have shown that expression of members of the C-X-C cytokine and vascular endothelial growth factor families such as IL-8, growth regulated oncogene-1 (Gro 1) and VEGF can promote angiogenesis, tumorigenesis and metastatic tumor progression. 1-3 The expression of multiple factors with proangiogenic activity by cancer cells poses a significant obstacle to effective therapy with agents targeted toward individual factors and receptors. Identification of common mechanism(s) underlying expression of such a diversity of factors could guide the development of therapy using fewer selective agents. We previously observed that IL-8, VEGF and other cytokines are coexpressed and often vary concurrently in serum and supernatants from cell lines from different patients with head and neck squamous cell carcinoma (HNSCC), 4,5 suggesting that these factors could be regulated by common signal pathways or transcription factors.Examination of the regulatory region of many proinflammatory cytokines and proangiogenic factors reveals that they share common promoter sites for transcription factors such as nuclear factor-B (NF-B) and/or activator protein-1 (AP-1), which can be activated by injury, cytokines and growth factors. 6 We found that differences in expression of these cytokines in different cancers was often related to differences in constitutive activation of both NF-B and AP-1. 6 Inhibition of NF-B activation by expression of a dominant negative inhibitor-B or pharmacologic agents was found to inhibit expression of IL-8 and other proinflammatory and proangiogenic cytokines, 7-10 as well as tumorigenesis and angiogenesis in vivo. 7,9 Inhibition of activation of extracellular signalregulated kinase (ERK) and AP-1 with antagonists of mitogenactivated/extracellular signal-regulated kinase (MEK) partially inhibited expression of both IL-8 and VEGF. 10 These results provided evidence that at least 2 signal pathways upstream of NF-B and AP-1 make important contributions to expression of these angiogenesis factors.We have recently examined the contribution of several factors that may contribute to upstream signal activation of NF-B and AP-1 and expression of IL-8 and VEGF. We found that IL-1␣ expressed by HNSCC promotes autocrine activation of NF-B and AP-1, expression of IL-8 and cell survival. 11 Expression of IL-1 receptor antagonist inhibited NF-B reporter activity and IL-8 expression by 60 -80%, indicating that IL-1␣ is a major contributor to constitutive activation of NF-B and IL-8. HNSCC were also found to express c-MET, a receptor tyrosine kinase for hepatocyte growth factor/scatter factor (HGF/SF). 12 Increased expression of HGF/SF was detected together with IL-8 and VEGF in serum of patients with HNSCC, and recombinant HGF and HGF from stromal fibroblasts was found to further induce IL-8 and VEGF expression by human HNSCC lines. Inhibitors of MEK and Abbreviations: AP-1, activator...

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Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 99%

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Bancroft

Chen

Yeh

et al. 2002

Intl Journal of Cancer

220

190

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“…Activation of Notch signaling by stably expressing exogenous NICD in human OSCC cell line can lead to growth arrest, accompanied by reduced β ‐catenin expression and dramatic increased p21 and p5360. EGFR is overexpressed or activated in premalignant ESCC lesions 62 and is correlated with poor prognosis in HNSCC patients 63, 64, 65, 66, 67. Notch inhibition by DNMAML1 promotes invasive growth of transformed esophageal epithelial cells with EGFR overexpression and p53 dysfunction 68.…”

Section: Notch Signaling In Head and Neck Squamous Cell Carcinoma (Hnmentioning

confidence: 99%

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

et al. 2016

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The role of Notch pathway in tumorigenesis is highly variable. It can be tumor suppressive or pro‐oncogenic, typically depending on the cellular context. Squamous cell carcinoma (SCC) is a cancer of the squamous cell, which can occur in diverse human tissues. SCCs are one of the most frequent human malignancies for which the pathologic mechanisms remain elusive. Recent genomic analysis of diverse SCCs identified marked levels of mutations in NOTCH1, implicating Notch signaling pathways in the pathogenesis of SCCs. In this review, evidences highlighting NOTCH's role in different types of SCCs are summarized. Moreover, based on accumulating structural information of the NOTCH receptor, the functional consequences of NOTCH1 gene mutations identified from diverse SCCs are analyzed, emphasizing loss of function of Notch in these cancers. Finally, we discuss the convergent view on an intriguing possibility that Notch may function as tumor suppressor in SCCs across different tissues. These mechanistic insights into Notch signaling pathways will help to guide the research of SCCs and development of therapeutic strategies for these cancers.

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“…40 The significance of EGFR as a high-risk indicator for disease progression or poor prognosis has been described for head and neck cancers. 8,11,21 In general, EGFR immunoreactivity is located in the cell membrane, but there is currently a debate on the interpretation of cytoplasmic staining of EGFR. 41 We included the cytoplasmic staining of EGFR in the results to be evaluated because this abnormal staining was assessed to be important and specific like membranous staining in another study of oral cancer.…”

Section: Molecular Marker Expression In Oral Cancer M Shiraki Et Almentioning

confidence: 99%

“…5,6 Epidermal growth factor receptor (EGFR), a transmembranous protein that binds to ligands such as EGF and transforming growth factor-a, activates protein-tyrosine kinase, which mediates the signaling involved in cell proliferation and differentiation. 7 Apart from the well-established prognostic indicators of TNM staging and mode of invasion, these markers have high prognostic values in human cancer, [8][9][10][11][12][13][14][15][16][17][18][19][20][21] although there are some discrepancies. [22][23][24] In view of the prospective impact of multiple molecular marker accumulation on tumor progression, multiple-marker testing could provide us with more useful information for our definition of the biological behavior of oral cancer than single marker expression.…”

mentioning

confidence: 99%

Combined expression of p53, cyclin D1 and epidermal growth factor receptor improves estimation of prognosis in curatively resected oral cancer

et al. 2005

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p53, cyclin D1 and epidermal growth factor receptor (EGFR) are molecular markers that regulate the cell cycle or cell growth and play important roles in tumor development and progression. In this study, we examined the impact of immunohistochemical expression of these markers on tumor progression in 140 oral cancers. p53, cyclin D1 and EGFR were expressed in 64 cases (46%), 54 cases (39%) and 54 cases (39%), respectively, but there was no inter-relationship between any two of these markers. In the association of these markers with clinicopathological features, EGFR expression alone was significantly associated with poor differentiation (P ¼ 0.0008) and invasive growth pattern (P ¼ 0.0003). Any of these markers, including EGFR, had no significant impact on survival. Coexpression of all these markers, however, was significantly associated with invasive growth pattern (P ¼ 0.0149) and shortened survival (P ¼ 0.0181), and was a significant and independent unfavorable prognostic factor (P ¼ 0.0002), along with tumor size (P ¼ 0.0040), nodal metastasis (P ¼ 0.0137) and growth pattern (P ¼ 0.0017) in a multivariate analysis. Simultaneous coexpression of these markers in oral cancers might prove to be a useful indicator for identification of low-or high-risk patients.

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Levels of TGF-α and EGFR Protein in Head and Neck Squamous Cell Carcinoma and Patient Survival

Abstract: Quantitation of EGFR and TGF-alpha protein levels in primary head and neck squamous cell carcinomas may be useful in identifying subgroups of patients at high risk of tumor recurrence and in guiding therapy.

Cited by 994 publications

References 43 publications

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines

Does Notch play a tumor suppressor role across diverse squamous cell carcinomas?

Combined expression of p53, cyclin D1 and epidermal growth factor receptor improves estimation of prognosis in curatively resected oral cancer

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