Two-step model of chemically induced carcinogenesis and proposed role of Stat3 in preventing tumorigenesis. Initiation is achieved by topical application of the carcinogen DMBA, which binds to DNA and typically induces mutations in the Ha-ras gene. The result of this process is the formation of an initiated cell. During this stage Stat3 protects the keratinocytes and the initiated cells from DNA damage–induced apoptosis. Promotion involves repeated application of a noncarcinogenic promoter, TPA, leading to clonal expansion of the initiated cell. This process results in the formation of multiple benign papillomas. Stat3 is essential for the proliferation of the initiated cells after TPA treatment and for the maintenance of the preoncogenic lesions. Progression is a spontaneous process characterized by the accumulation of additional genetic changes (i.e., elevated expression of genes encoding Ha-ras and cyclin D1; loss of functional p53), which accelerate the conversion of benign papillomas to malignant carcinomas. The pink cells represent initiated cells bearing Ha-ras mutations; the purple cells represent cells that have acquired multiple genetic changes.