epidermal-growth-factor and Neoplasms--Squamous-Cell

Squamous cell cancer of the head and neck is a debilitating disease. Combined modality treatments with surgery, chemotherapy, and radiation have been evaluated in multiple settings over the past 30 years. While surgery and radiation remain the potentially curative modalities, the addition of chemotherapy can in some cases decrease the rate of distant metastasis. When concurrent chemoradiation is employed, overall survival is improved, although toxicity can be higher. Studies have also shown a role for concurrent treatment in an effort to avoid total laryngectomy and preserve organ function. Multidisciplinary evaluation should be a routine part of care in this patient population. Future areas of research include the epidermal growth factor inhibitors, which have shown promise in early studies.

Topics: Antineoplastic Agents; Combined Modality Therapy; Epidermal Growth Factor; Evaluation Studies as Topic; Female; Humans; Laryngeal Neoplasms; Male; Neoplasms, Squamous Cell

Epidermal growth factor receptor (EGFR) overexpression correlates with recurrence and with treatment resistance in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to evaluate the relationship of EGFR gene copy number utilizing FISH and protein expression with automated quantitative analysis (AQUA) and to correlate those with patient outcome.. A tissue microarray composed of 102 HNSCC treated with (chemo)radiation was constructed and analyzed for EGFR copy number by FISH (Vysis; Abbott Laboratories) and EGFR protein expression using AQUA analysis of EGFR staining scored on a scale of 0 to 255. We evaluated associations of EGFR FISH status and AQUA score with clinicopathologic parameters and survival prognosis.. Eleven (17.2%) of 64 tumors with FISH results showed EGFR high polysomy and/or gene amplification (FISH positive). Protein levels assessed by AQUA in FISH-positive cases were significantly higher (P = 0.04) than in FISH-negative cases. Using the continuous AQUA scores for EGFR expression, AQUA and FISH showed significant agreement (Pearson's ρ = 0.353, P = 0.04). Patients with high tumor EGFR protein expression had inferior 5-year overall survival (27.7%) compared with those with low tumor EGFR expression (54%; P = 0.029). There was no significant association between EGFR FISH status and overall survival (P = 0.201). In the multivariate model, high tumor EGFR protein expression status remained an independent prognostic factor for overall survival (P = 0.047).. EGFR protein content correlates with gene copy number if protein content is quantitated and automatically analyzed, as with AQUA. EGFR protein levels assessed by AQUA strongly predict for patient outcome in HNSCC, whereas EGFR FISH status does not provide prognostic information.

Topics: Carcinoma; Carcinoma, Squamous Cell; Epidermal Growth Factor; Female; Gene Dosage; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms; Humans; In Situ Hybridization, Fluorescence; Male; Neoplasms, Squamous Cell; Predictive Value of Tests; Prognosis; Proteins; Squamous Cell Carcinoma of Head and Neck; Survival Analysis; Tissue Array Analysis

CD40 is expressed on basal keratinocytes and Squamous Cell Cancer of the Head and Neck (SCCHN) tumor cells in vivo and in vitro. CD40 ligation reduces proliferation of SCCHN cell lines and enhances EGFr mediated inhibition of proliferation. We investigated the mechanisms of CD40 function and EGFr cross-communication in SCCHN cell lines. CD40 ligation inhibited spontaneous and Fas-induced apoptosis. CD40 ligation specifically increased the secretion of IL-8, VEGF and PGE(2) but not IL-6, IL-10, FasL, GM-CSF, or TGFalpha. Co-ligation with EGFr further increased IL-8, VEGF and PGE(2) secretion. CD40 ligation also induced delayed activation and tyrosine phosphorylation of EGFr. CD40 induces secretion of specific proinflammatory and proangiogenic cytokines, inhibits spontaneous and Fas-induced apoptosis and increases EGFr phosphorylation. CD40 signaling may enhance the survival of SCCHN and tumor stroma.

Topics: Apoptosis; CD40 Antigens; CD40 Ligand; Cell Communication; Cell Line, Tumor; Cytokines; Epidermal Growth Factor; ErbB Receptors; Fas Ligand Protein; Head and Neck Neoplasms; Humans; Membrane Glycoproteins; Neoplasms, Squamous Cell; Phosphorylation; Prostaglandins

p63 is a homologue of p53 that functions to maintain progenitor cell populations in stratified epithelia. Delta Np63 alpha is overexpressed in epithelial cancers and has been shown to have oncogenic properties. We have previously reported that inhibition of epidermal growth factor receptor signaling results in a decrease in Delta Np63 alpha expression. Here, we demonstrate Delta Np63 alpha is a target of the phosphoinositide-3-kinase (PI3K) pathway downstream of the epidermal growth factor receptor. Treatment of keratinocytes with epidermal growth factor results in an increase in Delta Np63 alpha expression at the mRNA level, which is abrogated by inhibition of PI3K but not mitogen-activated protein kinase signaling. Small interfering RNA-mediated knockdown of the p110 beta catalytic subunit of PI3K results in a decrease in Delta Np63 alpha protein levels in keratinocytes. The results presented herein suggest that regulation of Delta Np63 alpha expression by the PI3K pathway plays a critical role in the survival and proliferative capacity of squamous epithelia.

Topics: Cell Line, Tumor; Cells, Cultured; DNA-Binding Proteins; Enzyme Inhibitors; Epidermal Growth Factor; Gene Expression Regulation; Humans; Keratinocytes; Neoplasms, Squamous Cell; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Subunits; RNA, Messenger; RNA, Small Interfering