Imaging Molecular Changes during Colon Tumorigenesis

University Of Pennsylvania, Philadelphia PA

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Abstract

Colorectal cancer remains the second leading cause of cancer-related deaths in the U.S. The development of chemoprevemive interventions for this disease continues to be facilitated by the elucidation of the genetic events required for colorectal tumor formation. These data, when combined with high-resolution imaging techniques and state-of-the-art genetic engineering tools, present a unique opportunity to develop novel systems for the in vivo evaluation of promising chemopreventive regimens. The hypothesis of the proposed studies is that alterations in the APC/beta-catenin/Tcfpathway are anaong the earliest changes that persist throughout colorectal tumorigenesis; imaging dysregulation of this pathway will allow us to identfy and follow colorectal lesions before they become malignant and refractory to chemopreventive intervention. This will be accomplished by establishing an optical imaging system to monitor the interaction of beta-catenin with Tcf within the colonic epithelium of Multiple Intestinal Neoplasia (FCCC Apc [Min]) mice. The FCCC Apc [Min] mice are well suited for the proposed studies since, unlike other Min strains, they develop multiple colorectal adenomas. In Specific Aim 1, beta-catenin activation will be characterized within the colonic mucosa of FCCC Apc [Min] mice either bearing a Tcf reporter construct or expressing the quail tva gene for the targeted retroviral delivery of "cancer genes" to colonic epithelial cells. Optical imaging techniques will be established and optimized in Specific Aim 2 for detecting the interaction of beta-catenin with Tcf in vitro as well as in colorectal lesions using a miniature endoscope coupled to a CCD camera. Specific Aim 3 focuses on the validation of the newly established in vitro and in rive imaging systems using sulindac sulfone; a chemopreventive agent known to restore membrane localization of beta-catenin and disrupt beta-catenin-mediated transcription. In Specific Aim 4, an image-based high-throughput screen will be conducted to identify additional compounds that can inhibit Tcf/beta-catenin activation. Utilization of these novel imaging procedures and mouse strains is anticipated to lead to the development of a highly efficacious regimen for the prevention of colorectal cancer or its recurrence in high-risk individuals. Based on the presence of dysregulated beta-catenin signaling in approximately 90% of all colorectal cancers, the impact of such a chemopreventive regimen on colorectal tumor incidence could be far-reaching.