The upper aerodigestive tract is predisposed to the formation of multiple p
rimary tumors due to field cancerization. TGF-alpha/EGFR autocrine signalin
g appears to play an important role in squamous cell carcinoma of the head
and neck (SCCHN) and upregulation of TGF-alpha and EGFR is an early event i
n SCCHN carcinogenesis. STAT proteins, including Stat3, are activated by TG
F-alpha and EGFR and strategies that downmodulate TGF-alpha or EGFR inhibit
SCCHN cell proliferation and abrogate Stat3 activation. Targeting Stat3 le
ads to SCCHN growth inhibition, increases apoptosis and a downmodulation of
Bcl-x(L) expression in head and neck tumors. These studies support the rol
e of Stat3 as an oncogene, which is activated early in SCCHN carcinogenesis
, and efforts to understand EGFR-mediated Stat3 signaling could facilitate
novel strategies that will interfere with this growth promoting pathway.