Squamous Cell Carcinoma and Topographic Cuing

描述(申请人提供)：肿瘤转化导致功能障碍或缺乏对环境线索的反应，其整合导致维持正常细胞的动态平衡。我们的实验室和其他实验室的工作表明，基底膜具有复杂的三维地形，由交织的纤维、孔洞和高度组成，尺寸范围在20-400 nm之间。具有生物相关纳米和亚微米范围特征的合成基质对细胞定位、细胞黏附、迁移、增殖和细胞内信号蛋白的调节具有最大的影响。这项建议的总体目标是调查纳米级(100 Nm)和亚微米(100 nm-1微米)的地形特征，即基底膜的特征，对正常、永生化和转化(致癌)的角质形成细胞行为的影响。初步数据表明，与原代培养的角质形成细胞相比，转化的角质形成细胞对地形提示没有或仅有微弱的反应。我们还产生了数据，表明细胞内信号通路在转化细胞培养物和原代细胞培养物中受到不同的调节。我们推测，转化细胞对地形提示的反应改变可能是角质形成细胞肿瘤性转化的重要组成部分。我们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受控制造，具有生物相关的特征类型、尺寸和分布，以不同的方式调节正常、永生化和致癌的角质形成细胞的行为。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)患者的基底膜的形态是什么？2.从纳米到微尺度的形态特征对正常、永生化和转化的角质形成细胞的形态、取向、黏附、迁移、增殖和分化等行为有何影响？3.在原代、永生化的非致瘤和转化的致癌角质形成细胞中，地形提示是否对细胞内信号通路进行了差异调节？地形图提示可能改变恶性表型，或对地形图提示的反应可能预测转移潜能，并可能识别用于治疗干预的新的分子靶点。

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.