The rising incidence of skin cancer and its associated mortality, deformity, and medical costs represent a major public health concern. There is a pressing need for a better understanding of the molecular basis for what triggers incipient cancer cells to develop into tumors. We have demonstrated that polyamines play an essential role in the early promotional phase of skin tumorigenesis by activating not only epithelial cells but also underlying stromal cells. Ornithine decarboxylase (ODC) is a key regulatory enzyme in the biosynthesis of polyamines, which are essential for normal cell growth and differentiation. De novo induction of ODC activity in the suprabasal epidermis produces a phenotype similar to that in wounded skin, with stimulated proliferation of basal epidermal cells, neoangiogenesis, and increased production of extracellular matrix proteins. However, there have been no studies to determine whether polyamines create a permissive stromal microenvironment needed for tumor growth, nor the signaling pathways that mediate the strong tumor promoting effects of polyamines. We postulate that polyamines promote skin tumorigenesis through activation of keratinocyte stem cells and dermal stromal cells and is mediated via polyamine-stimulation of the Akt signaling pathway, stabilization of beta-catenin, and activation of Tcf-dependent transcription. To investigate whether early in vivo changes in polyamine levels activate these signaling pathways to trigger the expansion of dormant, genetically altered epidermal cells into skin tumors, we propose using novel conditional mouse models to: 1. Identify target cells responsible for polyamine-promoted skin tumorigenesis by A. Assessing the effect of polyamines on stem cells B. Investigating the role of underlying stromal cells 2. Examine the involvement of the PI3K/Akt/mTOR pathway in the polyamine-activation of A. nontumor-bearing skin B. skin tumorigenesis C. skin vascularization. 3. Investigate the involvement of beta-catenin-Tcf-dependent transcription in the polyamine activation of keratinocytes and dermal fibroblasts. 4. Examine whether polyamines and activation of putative downstream effector pathways play a role in early human skin tumorigenesis. The overall goal is to identify the mechanism(s) by which elevated levels of polyamines alter environmental signals to trigger the proliferation of epidermal stem cells possessing genetic lesions in order to better design rational approaches to prevent cutaneous neoplasia. ? ? ?
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