Gastric carcinoma is a leading cause of cancer mortality worldwide. The genetic changes underlying the development of gastric cancer remain largely unknown. In human samples, it is rather rare to detect dysplastic lesions since most patients are diagnosed with cancers already at an advanced stage. We have recently obtained and confirmed a trefoil factor-1 (TFF1) knockout (-/-) mouse model that develops a well characterized pre-neoplastic gastric dysplasia similar to the human gastric disease. Thus, this unique TFF1 -/- mouse model provides us a unique opportunity to explore the molecular alterations in precancerous dysplasia and allows for the discovery of novel molecular targets. These targets will improve our diagnostic tools and provide further insight into the molecular biology of early gastric tumorigenesis that is unknown. Thus, we hypothesize that TFF1 -/- mice acquire unique molecular alterations similar to those in human gastric tumorigenesis. The molecular alterations that lead to the development of gastric neoplasia will be elucidated in premalignant dysplastic lesions for discovery of biomarkers and molecular targets of early gastric tumorigenesis.
AIM#1. DISCOVERY OF MOLECULAR TARGETS IN EARLY GASTRIC TUMORIGENESIS:
We aim to perform a comprehensive transcriptome and proteome profile of dysplastic gastric lesions in the TFF1-/- mouse model of intestinal gastric cancer. A similar approach has been successfully used to identify serum biomarkers in pre-invasive pancreatic cancer mouse model. a) SERUM PROTEOMIC PROFILING The need to develop non-invasive assay based on serum biomarkers for early detection of this deadly disease will be explored under this aim, employing proteomic approach in sera obtained from mice with and without dysplasia. b) COMPREHENSIVE PROTEOME ANALYSES We will employ proteomic approach using high-resolution two-dimensional gel and peptide mass-spectrometry (MS) in mice with and without dysplasia. c) COMPREHENSIVE TRANSCRIPTOME ANALYSES We will employ gene expression analyses using the most comprehensive mouse gene array chip on dissected stomach tissues from mice with and without dysplasia (TFF1 -/- and TFF1 +/+, respectively).
AIM #2. VALIDATION AND COMPARISON WITH HUMAN GASTRIC CANCER: We have generated a transcriptome map of human gastric cancers and established a tumor tissue bank and database. These tools provide us an exceptional opportunity to perform initial comparison and validation of the molecular targets that will be identified in dysplasia of TFF1 -/- mice under aim #1.
