Polyamines and Epithelial tumorigenesis

描述（由申请人提供）：皮肤癌的发病率及其相关的死亡率，畸形和医疗费用的上升代表了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了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发挥重要作用，不仅激活上皮细胞，但也底层基质细胞。鸟氨酸脱羧酶（ODC）是多胺生物合成的关键调节酶，多胺对细胞的正常生长和分化至关重要。从头诱导ODC活性的基底上表皮产生的表型类似于在受伤的皮肤，刺激增殖的基底表皮细胞，新血管生成，并增加生产的细胞外基质蛋白。然而，还没有研究来确定多胺是否产生肿瘤生长所需的允许的基质微环境，也没有介导多胺的强肿瘤促进作用的信号通路。我们推测多胺通过激活角质形成细胞干细胞和真皮基质细胞促进皮肤肿瘤发生，并通过多胺刺激Akt信号通路、稳定β-连环蛋白和激活Tcf依赖性转录介导。为了研究多胺水平的早期体内变化是否激活这些信号通路以触发休眠的、遗传改变的表皮细胞扩展成皮肤肿瘤，我们提出使用新的条件性小鼠模型：1.鉴定多胺促进皮肤肿瘤发生的靶细胞。评估多胺对干细胞B的影响。研究潜在基质细胞的作用2.检查PI 3 K/Akt/mTOR通路在A.非肿瘤皮肤B。皮肤肿瘤发生C.皮肤血管化3.研究β-连环蛋白-Tcf依赖性转录参与角质形成细胞和真皮成纤维细胞的多胺活化。4.检查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病变的表皮干细胞增殖的机制，以便更好地设计合理的方法来预防皮肤瘤形成。

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.