Squamous Cell Carcinoma and Topographic Cuing

描述（由申请人提供）：肿瘤转化导致对环境线索的功能障碍或缺乏反应，环境线索的整合导致正常细胞内稳态的维持。在我们的实验室和其他人进行的工作表明，基底膜具有复杂的三维地形组成的交织纤维孔和海拔在20-400纳米的尺寸范围。具有生物学相关纳米级和亚微米范围特征的合成基质对细胞定向、细胞粘附、迁移、增殖和细胞内信号蛋白的调节具有最大影响。本提案的总体目标是研究纳米级（< 100 nm）和亚微米级（100 nm-1 um）地形特征（基底膜特征）对正常、永生化和转化（致瘤性）角质形成细胞行为的影响。初步数据表明，转化的角质形成细胞未能响应或响应只有微弱的地形线索相比，原代培养的角质形成细胞。我们还生成了表明细胞内信号传导途径在转化细胞培养物与原代细胞培养物中被差异调节的数据。我们推测，改变了地形线索的转化细胞的反应可能是角质形成细胞的肿瘤转化的一个重要组成部分。我们已经组建了一个强大的跨学科团队来测试以下假设：完全合成的表面可以通过控制制造进行工程设计，具有生物相关的特征类型，尺寸和分布，差异调节正常，永生化和致癌的角质形成细胞行为。我们将解决以下问题：1.正常角质形成细胞和鳞状细胞癌（SCC）患者的基底膜的拓扑结构是什么？2.纳米尺度到微米尺度的地形特征对正常、永生化和转化的角质形成细胞行为有什么影响，包括形态、定向、粘附、迁移、增殖和分化？3.地形提示是否差异调节原代、永生化的非致瘤性和转化的致瘤性角质形成细胞的细胞内信号通路？地形线索可能会改变恶性表型或地形线索的反应可能是预测转移的潜力，并可能确定新的分子靶点的治疗干预。

DESCRIPTION (provided by applicant): Neoplastic transformation results in dysfunctional or lack of response to the environmental cues whose integration results in the maintenance of homeostasis in normal cells. Work performed in our laboratories and others have demonstrated that basement membranes possess a complex three-dimensional topography consisting of interwoven fibers pores and elevations in the 20-400 nm size range. Synthetic matrices with features in the biologically relevant nanoscale and sub-micron range have the greatest impact on cell orientation, cell adhesion, migration, proliferation and modulation of intracellular signaling proteins. The overall goal of this proposal is to investigate the impact of nanoscale (< 100 nm) and submicron (100 nm-1um) topographic features, characteristic of basement membranes, on normal, immortalized and transformed (tumorigenic) keratinocyte behavior. Preliminary data suggest that transformed keratinocytes fail to respond or respond only weakly to topographic cues compared to primarily cultured keratinocytes. We have also generated data that suggest intracellular signaling pathways are differentially modulated in transformed vs primary cell cultures. We hypothesize that the altered response of transformed cells to topographic cues may be an essential component in the neoplastic transformation of keratinocytes. We have assembled a strong interdisciplinary team to test the following hypothesis: Totally synthetic surfaces can be engineered through controlled fabrication with biologically relevant feature types, dimensions and distributions that differentially modulate normal, immortalized and carcinogenic keratinocyte behaviors. We will address the following questions: 1.What is the topography of the basement membrane underlying normal keratinocytes and from patients with squamous cell carcinoma (SCC)? 2. What are the effects of nanoscale to microscale topographic features on normal, immortalized and transformed keratinocyte cell behaviors including morphology, orientation, adhesion, migration, proliferation and differentiation? 3.Does topographic cueing differentially modulate intracellular signaling pathways in primary, immortalized non-tumorigenic and transformed tumorigenic keratinocytes? Topographic cues may alter the malignant phenotype or the response to topographic cues may be predictive of metastatic potential and may identify novel molecular targets for therapeutic intervention.