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.
