3D-adhesion stromagenesis in cancer permissiveness

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屏障。 虽然这种屏障功能在早期肿瘤发展中仍然存在，但它可以在肿瘤发生的后期阶段逆转，并且基质被颠覆或“激活”以参与肿瘤发展。 该过程如何发生尚不清楚，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，其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一个原因是我们缺乏合适的生理实验系统。 为此，我们开发了一种新的体内样3D基质系统，其来源于癌症发展进行性阶段的成纤维细胞。 在正常和肿瘤相关基质的初步比较中，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，我们假设活化的基质成纤维细胞内改变的附着信号有助于肿瘤相关基质的肿瘤促进特性。 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断癌症进展。 为了验证这些假设，我们提出了两个目标。 目的1将检验整合素依赖性Src和FAK信号通路的改变对肿瘤促进基质的发展至关重要的假设。 目的2将测试的假设，上皮肿瘤细胞的侵袭，可以通过靶向的基本stromagenic信号转导途径抑制。 完成拟议的研究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抑制上皮肿瘤转化或导致肿瘤消退的见解。 最终，我们的长期目标是靶向肿瘤相关基质，从而将癌症作为一种无害的慢性疾病。

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.