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（由申请人提供）：在正常组织中，基质提供了限制上皮细胞生长的抑制障碍。 尽管这种屏障功能仍然存在于早期肿瘤的发展中，但可以在肿瘤发生的晚期阶段逆转，而基质被颠覆或“激活”以参与肿瘤的发育。 该过程的发生方式尚不清楚，但被认为涉及基质成纤维细胞的变化，基质中的主要细胞类型会产生和修饰基质细胞外基质（ECM）。 我们对基质激活知之甚少的原因之一是我们缺乏合适的生理实验系统。 为此，我们开发了一种新型的体内3D基质系统，该系统源自癌症发展的渐进阶段的成纤维细胞。 在正常和肿瘤相关的基质的最初比较中，我们观察到成纤维细胞及其分泌的ECM的结构和生化改变。 基于这些初步数据，我们假设在活化的基质成纤维细胞内改变了附着信号传导，这有助于促进与肿瘤相关的基质的肿瘤促进特性。 我们还建议，抑制这些信号可以通过恢复正常基质的肿瘤抑制特性来阻断癌症的进展。 为了检验这些假设，我们提出了2个目标。 AIM 1将检验以下假设：整联蛋白依赖性SRC和FAK信号通路的改变对于促进肿瘤基质的发展至关重要。 AIM 2将检验以下假设：上皮肿瘤细胞侵袭可以通过靶向基本的浮动物信号传导途径来抑制。 拟议的研究的完成应有助于我们更好地了解基质激活的过程，并提供有关如何操纵该过程以包含上皮肿瘤转化或引起肿瘤退化的见解。 最终，我们的长期目标是针对与肿瘤相关的基质，从而将癌症保持为无害的慢性疾病。