Primed Stroma: A Tumor Permissive Microenvironment

描述（由申请人提供）：本研究的长期目标是揭示基质成纤维细胞及其细胞外基质促进肿瘤进展的分子特征和机制。 转化细胞和正常细胞之间的根本区别之一是它们与周围环境相互作用的方式;探索这些差异对于理解癌症进展的病理生物学至关重要。 我们的假设是基于这样的观察：上皮肿瘤细胞将信息传递到周围的间充质基质，触发一系列事件，导致基质的修饰，使其为肿瘤进展做好准备或允许。 我们的假设假定存在结构、生化和/或机械畸变，其表现为“致敏基质”内的修饰的粘附结构。“这些异常或修饰的结构支持甚至可能引发肿瘤进展。 触发基质引发的事件以及引发和支持肿瘤进展的“引发基质”内的结构动力学大多是未知的，这在很大程度上是由于缺乏合适的生理学相关的实验系统。 我们最近利用三维细胞衍生的培养系统来分析粘附结构和信号转导，让人联想到体内粘附。 这样的3D矩阵系统非常接近“正常基质”，我们的初步结果的特点是在这个“正常基质”的粘附结构和信号事件。“此外，我们能够产生3D基质，这些基质来源于与不同进展阶段的肿瘤相关的成纤维细胞。 根据这一建议，我们希望建立并表征体内类似渐进性基质衍生的3D微环境系统，以揭示导致肿瘤进展中基质容许性的事件。 因此，我们建议研究进展性基质衍生的3D微环境的特征和肿瘤容许性。 本文提出的研究的成功完成将有助于建立一个未来的研究的基础上分析的关键细胞粘附结构，其分子特征，和信号级联支持肿瘤进展的手段，我们在体内的三维基质系统。 我们的最终目标是开发治疗方法，重点是将癌症作为一种慢性和无害的疾病。

DESCRIPTION (provided by applicant): The long-term goal of this study proposes to uncover the molecular characteristics and mechanisms by which stromal fibroblasts and their extracellular matrix contribute to neoplastic progression. One of the fundamental differences between transformed and normal cells is the manner in which they interact with their immediate environment; exploring these differences is critical for understanding the pathobiology of cancer progression. We based our hypothesis on the observation that epithelial tumor cells transmit information to the surrounding mesenchymal stroma, triggering a chain of events resulting in modification of the stroma, rendering it primed or permissive for tumor progression. Our hypothesis posits the existence of architectural, biochemical, and/or mechanistic aberrations that manifest as modified adhesion structures within the 'primed stroma.' These aberrant or modified structures support or perhaps even incite tumor progression. The events that trigger stromal priming and the structural dynamics within 'primed stroma' that incite and support tumor progression are mostly unknown, in large part due to lack of a suitable, physiologically relevant experimental system. We have recently exploited three dimensional cell-derived culture systems to analyze adhesion structures and signal transduction reminiscent of in vivo adhesions. Such 3D matrix systems closely approximate 'normal stroma'; our preliminary results have characterized the adhesion structures and signaling events within this 'normal stroma.' Moreover, we are capable of producing 3D matrices that are derived from fibroblasts associated to tumors at diverse stages of progression. On this proposal, we would like to establish and characterize in vivo-like progressive stromal-derived 3D microenvironmental systems for the uncovering of the events leading to stroma permissiveness in neoplastic progression. Hence, we propose to study the characteristics and tumor permissiveness of progressive stroma-derived 3D microenvironments. The successful accomplishment of the studies herein proposed will facilitate establishment of a future study based on the analysis of crucial cell-adhesion structures, their molecular signature, and signaling cascades supporting tumor progression by means of our in vivo-like 3D stromal-systems. Developing therapeutic approaches focusing on containing cancer as a chronic and innocuous disease is our ultimate goal.