Polyamines and Epithelial tumorigenesis

描述(由申请人提供)：皮肤癌发病率的上升及其相关的死亡率、畸形率和医疗费用是一个主要的公共卫生问题。迫切需要更好地了解是什么触发早期癌细胞发展成肿瘤的分子基础。我们已经证明，多胺在皮肤肿瘤发生的早期促进阶段扮演着重要的角色，它不仅激活了皮肤上皮细胞，而且还激活了潜在的基质细胞。鸟氨酸脱羧酶(ODC)是多胺生物合成的关键调节酶，对细胞的正常生长和分化是必不可少的。从头开始诱导基底上表皮中的ODC活性产生与创伤皮肤相似的表型，刺激基底表皮细胞的增殖，新生血管的形成，并增加细胞外基质蛋白的产生。然而，还没有研究确定多胺是否创造了肿瘤生长所需的允许的间质微环境，也没有研究多胺介导强大的促肿瘤作用的信号通路。我们推测，多胺通过激活角质形成干细胞和真皮基质细胞促进皮肤肿瘤的发生，并通过多胺刺激Akt信号通路、稳定β-连环蛋白和激活依赖于Tcf的转录来介导。为了研究体内早期多胺水平的变化是否激活了这些信号通路，从而触发了休眠的、基因改变的表皮细胞向皮肤肿瘤的扩张，我们建议使用新的条件小鼠模型：1.通过A.评估多胺对干细胞的影响来识别负责多胺促进皮肤肿瘤发生的靶细胞；B.调查潜在的基质细胞的作用2.研究PI3K/Akt/mTOR通路在多胺激活非肿瘤皮肤B.皮肤肿瘤发生C.皮肤血管形成中的作用。3.研究β-连环蛋白-Tcf依赖的转录在角质形成细胞和真皮成纤维细胞多胺激活中的作用。4.研究多胺和下游效应通路的激活是否在早期人类皮肤肿瘤发生中起作用。总体目标是确定多胺水平升高改变环境信号以触发具有遗传损伤的表皮干细胞增殖的机制(S)，以便更好地设计合理的方法来预防皮肤肿瘤。

DESCRIPTION (provided by applicant): 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.