Loss of Smad signaling in human colorectal cancer is associated with advanced disease and poor prognosis

PURPOSE - Based largely on in vitro investigations and animal studies, investigators believe that disruptions of transforming growth factor-beta (TGF-beta) signaling contribute to the development and progression of human colorectal cancer. The purpose of this study was to directly assess the status of the TGF-beta signaling pathway in colorectal cancer and determine the effects of its disruption on clinical behavior and outcome. MATERIALS AND METHODS - Smad proteins are the principal intracellular components of the TGF-beta signaling pathway. We conducted a high-throughput analysis of the expression patterns of Smad2, phosphorylated (activated) Smad2 (pSmad2), and Smad4 in more than 600 human colorectal cancer specimens assembled in tissue microarrays. RESULTS - The vast majority (93.8%; 95% CI: 92%-96%) of colorectal cancers expressed phosphorylated Smad2, indicating the ability of the tumors to survive and proliferate within a microenvironment that contains bioactive TGF-beta. Twelve of 633 (1.9%; 95% CI: 1%-3%) cases failed to express Smad2, and 15 of 641 (2.3%; 95% CI: 1%-4%) cases failed to express Smad4. Moreover, 29 of 615 (4.7%; 95% CI: 3%-7%) of cases expressed Smad2 but not its activated form (pSmad2), suggesting the presence of a TGF-beta receptor defect. Based on an analysis of 577 cases for which clinical outcome information was available, failure to express Smad2, pSmad2, orSmad4 was associated with advanced-stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months). DISCUSSION - Loss of Smad activation and/or expression occurs in approximately 10% of colorectal cancers. This subset has a poor prognosis because of its association with advanced disease and the presence of lymph node metastases at diagnosis.