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Tumor Biology |
Tumor Biology and Metastasis Group, Section of Cancer Therapeutics, The Institute of Cancer Research, Sutton, Surrey, SM2 5NG [P. O-c., W. J. C., G. M. B., S. A. E.]; European Institute of Health and Medical Sciences, University of Surrey, Guildford, GU2 5XH [H. M.]; and Department of Head and Neck Surgery, Royal Marsden Hospital, London, SW3 6JJ [P. O-c., P. R-E.]; United Kingdom
Head and neck squamous cell carcinomas (HNSCCs) are characterized
by a marked propensity for local invasion and dissemination to cervical
lymph nodes, with distant metastases developing in 30–40% of cases.
Overexpression of the epidermal growth factor receptor
(EGFR/c-erbB-1) and/or its ligands and high levels of
certain matrix metalloproteinases (MMPs) have been associated with poor
prognosis. The aim of this study was to examine the effects of EGFR
ligands on gelatinase expression and invasion in HNSCC cell lines. We
tested epidermal growth factor (EGF), transforming growth factor 
,
betacellulin, heparin-binding EGF, and amphiregulin and measured
expression of gelatinases MMP-9 and MMP-2 in an established squamous
carcinoma cell line (Detroit-562) and in two cell lines newly derived
from patients with head and neck cancers (SIHN-005A and SIHN-006).
Incubation of the cell lines with EGF-like ligands up-regulated MMP-9
(but not MMP-2) expression as measured by semiquantitative reverse
transcription-PCR in a dose-dependent manner, with the effects being
most marked in cells with high EGFR levels and undetectable in cells
with low levels. Maximum stimulation was obtained in a concentration
range of 10–100 nM. In addition, we confirmed by
zymography that gelatinolytic activity consistent with MMP-9
(Mr 92,000) was up-regulated in parallel with
increases in gene expression. Betacellulin (which binds both to EGFR
and c-erbB-4 receptors) consistently increased MMP-9
expression and activation to a significantly greater degree than the
other four ligands when tested at equimolar concentrations. In parallel
with MMP-9 up-regulation, all EGF-like ligands increased tumor cell
invasion through Matrigel in in vitro Transwell assays.
These activities were independent of ligand effects on cell
proliferation. Antagonist (ICR62) or agonist (ICR9) anti-EGFR
monoclonal antibodies, respectively, inhibited or potentiated MMP-9
activity and tumor cell invasion induced by all ligands. Furthermore, a
monoclonal antibody that neutralizes MMP-9 activity (Ab1) also
inhibited ligand-induced invasion of HNSCC. We confirmed that tumor
cell lines used in these studies (and a larger series not reported
here) generally expressed multiple c-erbB receptors and
ligands. These results indicate that autocrine or paracrine signaling
through EGFR potentiates the invasive potential of HNSCC via the
selective up-regulation and activation of MMP-9. Furthermore, ligands
such as betacellulin (which is commonly expressed in HNSCC), which can
bind to and activate other c-erbB receptors, may be
especially potent in this regard.
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