epidermal-growth-factor and Pharyngeal-Neoplasms

Topics: Cancer Vaccines; Epidermal Growth Factor; Genetic Therapy; Humans; Mouth Neoplasms; Pharyngeal Neoplasms

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.

Topics: Antibodies, Monoclonal; Betacellulin; Carcinoma, Squamous Cell; Cell Division; Culture Media, Conditioned; Enzyme Induction; Epidermal Growth Factor; ErbB Receptors; Gene Expression Regulation, Neoplastic; Growth Substances; Head and Neck Neoplasms; Humans; Intercellular Signaling Peptides and Proteins; Ligands; Metalloendopeptidases; Neoplasm Invasiveness; Neoplasm Proteins; Neuregulin-1; Pharyngeal Neoplasms; Phenotype; Receptor, ErbB-2; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tumor Cells, Cultured

We have characterized 24 hypopharyngeal squamous cell carcinomas and 5 normal hypopharyngeal tissues by immunostaining with antibodies against epidermal growth factor (EGF), EGF-Receptor (EGFR), p53, v-erb B, and ras p21. The Avidin-Biotin Complex (ABC) technique was employed. Overexpression of p53 appeared in 17 of 24 cases of squamous cell carcinoma of the hypopharynx (normal mucosa: none, well differentiated: 60%, moderately differentiated: 71.4%, poorly differentiated: 71.4%). Some dysplastic mucosae surrounding cancer lesions showed overexpression of p53. EGF and EGFR tended to be expressed more strongly in carcinoma [EGF: 29.1% (well differentiated: 30%, moderately differentiated: 28.6%, poorly differentiated: 28.6%); EGFR: 50% (well differentiated: 60%, moderately differentiated: 42.9%, poorly differentiated: 42.9%)] than in normal mucosa (EGF: 0%, EGFR: 20%). The v-erb B stained positively in carcinoma [62.5% (well differentiated: 70%, moderately differentiated: 71.4%, poorly differentiated: 42.9%)] but negatively in normal mucosa. These data suggest that genetic mutations of p53 probably play an important role at an early stage of tumorigenesis, and that the networks of EGF, EGFR and v-erb B probably are involved in the development of hypopharyngeal squamous cell carcinoma.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Hypopharynx; Immunohistochemistry; Male; Middle Aged; Oncogene Proteins v-erbB; Pharyngeal Neoplasms; Proto-Oncogene Proteins p21(ras); Tumor Suppressor Protein p53

Suramin, a drug used for the treatment of African trypanosomiasis and onchoceriasis, has potential anti-cancer activity. As to the mechanism of action, it is considered to interfere with the action of tumor growth factor and specific growth enzymes. In the present study, the effect of suramin on proliferation of human head and neck squamous cell carcinoma cells was determined. A significant growth inhibition in all three cell lines tested was observed when the concentration of suramin was 100 micrograms/ml or more. The hypothesis was tested to ascertain whether growth inhibition may be due to selective interference with the action of epidermal growth factor. Suramin at growth inhibiting concentrations only partly antagonized the growth stimulating effect of EGF indicating that other mechanisms of action may also contribute to the growth inhibitory activity of suramin. Furthermore, evidence was found that serum proteins other than growth factors presented in the culture medium have a growth stimulating effect on cells and a strongly antagonistical effect on suramin activity.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Division; Dose-Response Relationship, Drug; Epidermal Growth Factor; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Mouth Neoplasms; Pharyngeal Neoplasms; Serum Albumin, Bovine; Suramin; Tumor Cells, Cultured