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


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, or Smad4 was associated with advanced-stage disease, the presence of lymph node metastases, and a significantly shorter overall survival (median survival: 35 vs 58 months).


CONCLUSIONS
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.
Xie
Wen
W
Division of Medical Oncology, Department of Internal Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Rimm
David L
DL
Lin
Yong
Y
Shih
Weichung J
WJ
Reiss
Michael
M
D002455:Cell Division; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D011379:Prognosis; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D016019:Survival Analysis; D015534:Trans-Activators / Q000096:biosynthesis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta