Constitutive activation of Stat3 signaling abrogates apoptosis in squamouscell carcinogenesis in vivo

Field cancerization predisposes the upper aerodigestive tract mucosa to the formation of multiple primary tumors, when exposed to environmental carcin ogens. Up-regulation of epidermal growth factor receptor occurs early in sq uamous cell carcinogenesis and is critical for the loss of growth control i n a variety of human cancers, including head and neck squamous cell carcino mas. In these tumor cells in culture, epidermal growth factor receptor stim ulation initiates signaling via persistent activation of selective STAT pro teins. To determine the timing of Stat3 activation in head and neck carcino genesis, we studied the expression and constitutive activation of Stat3 in tumors and normal mucosa from patients with head and neck cancer compared w ith mucosa from controls without cancer. Stat3 was up-regulated and constit utively activated in both primary human head and neck tumors as well as in normal mucosa from these cancer patients compared with control normal mucos a from patients without cancer. In vivo liposome-mediated gene therapy with a Stat3 antisense plasmid efficiently inhibited Stat3 activation, increase d tumor cell apoptosis, and decreased Bcl-x(L) expression in a head and nec k xenograft model. These findings provide evidence that constitutively acti vated Stat3 is an early event in head and neck carcinogenesis that contribu tes to the loss of growth control by an anti-apoptotic mechanism.