3D-adhesion stromagenesis in cancer permissiveness

癌症许可性中的 3D 粘附基质发生

• 批准号: 7142995
• 负责人: Edna Cukierman
• 金额: $ 24.28万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142995
• 关键词: adhesions; fibroblasts; integrins; neoplasm /cancer

DESCRIPTION (provided by applicant): In normal tissue, the stroma provides an inhibitory barrier to restrict epithelial cell growth. While this barrier function remains in early tumor development, it can be reversed during later stages of tumorigenesis, and the stroma subverted or "activated" to participate in tumor development. How this process occurs is not known, but is thought to involve changes in the stromal fibroblasts, the predominant cell type in the stroma, which produce and modify the stromal extracellular matrix (ECM). One reason that we know so little about stromal activation is that we lack a suitable physiologic experimental system. To that end, we have developed a novel in vivo-like 3D stromal system derived from fibroblasts at progressive stages of cancer development. In initial comparisons of normal and tumor-associated stroma, we have observed structural and biochemical alterations in both fibroblasts and their secreted ECMs. Based on these preliminary data, we hypothesize that altered attachment signaling within the activated stromal fibroblasts contributes to the tumor promoting properties of the tumor-associated stroma. We also propose that inhibiting these signals can block cancer progression by restoring the tumor-repressive property of normal stroma. To test these hypotheses, we propose 2 aims. Aim 1 will test the hypothesis that alterations in the integrin-dependent Src and FAK signaling pathway are critical to the development of tumor-promoting stroma. Aim 2 will test the hypothesis that epithelial tumor-cell invasion can be repressed by targeting the fundamental stromagenic signaling pathways. The completion of the proposed studies should assist us to better understand the process of stromal activation, and provide insights into how to manipulate the process to contain epithelial tumor transformation or cause tumor regression. Ultimately, our long-term goal is to target the tumor-associated stroma thus maintaining cancer as an innocuous chronic disease.

描述(申请人提供)：在正常组织中，基质提供了一种抑制屏障来限制上皮细胞的生长。虽然这种屏障功能仍然存在于肿瘤发展的早期，但在肿瘤形成的后期阶段，它可以被逆转，基质被颠覆或“激活”，参与肿瘤的发展。这一过程是如何发生的尚不清楚，但被认为涉及基质成纤维细胞的变化，基质成纤维细胞是基质中的主要细胞类型，它产生和修改基质细胞外基质(ECM)。我们对间质激活知之甚少的一个原因是我们缺乏合适的生理学实验系统。为此，我们开发了一种新的类似活体的3D基质系统，该系统来自癌症进展阶段的成纤维细胞。在与正常和肿瘤相关间质的初步比较中，我们观察到成纤维细胞及其分泌的细胞外基质的结构和生化变化。基于这些初步数据，我们假设，激活的间质成纤维细胞内连接信号的改变有助于肿瘤相关间质的促癌特性。我们还提出，抑制这些信号可以通过恢复正常间质的肿瘤抑制特性来阻止癌症的进展。为了检验这些假设，我们提出了两个目标。目的1验证整合素依赖的Src和FAK信号通路的改变对促进肿瘤间质的发展至关重要的假设。目的2将验证上皮性肿瘤细胞侵袭可以通过靶向基本的基质生成信号通路来抑制的假说。拟议研究的完成将有助于我们更好地了解间质激活的过程，并为如何操纵这一过程以遏制上皮性肿瘤的转化或导致肿瘤的消退提供见解。最终，我们的长期目标是针对与肿瘤相关的间质，从而保持癌症是一种无害的慢性病。