Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands.
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.
O-charoenrat
P
P
Department of Head and Neck Surgery, Royal Marsden Hospital, London, UK. pornchai@icr.ac.uk
Rhys-Evans
P
P
Court
W J
WJ
Box
G M
GM
Eccles
S A
SA
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D066259:Betacellulin; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D017077:Culture Media, Conditioned; D004790:Enzyme Induction / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006133:Growth Substances / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000503:physiopathology* / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020890:Neuregulin-1 / Q000494:pharmacology*; D010610:Pharyngeal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D066259:Betacellulin; D017077:Culture Media, Conditioned; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008666:Metalloendopeptidases; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; C587851:BTC protein, human; C087230:heregulin beta1