Abstract
Background: Loss of epithelial morphology and the acquisition of mesenchymal characteristics may contribute to metastasis formation during colorectal tumorigenesis. The Wnt, Notch and TGFβ signaling pathways control tissue homeostasis and tumor development in the gut. The relationship between the activity of these pathways and the expression of epithelial and mesenchymal markers was investigated in a series of primary colorectal tumors and their corresponding metastases. Methods: Tissue samples of primary colorectal tumors, normal colonic mucosa, and regional and systemic metastases were processed for immunohistochemistry in a tissue microarray format. The expression of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin) markers was related to markers of Wnt (β-catenin), Notch (HES1) and TGFβ (phospho-SMAD2) signalling. In addition, the KRAS mutation status was assessed. Results: When compared to normal mucosa, primary colorectal tumors showed a marked increase in the levels of cytoplasmic vimentin and nuclear β-catenin, phospho-SMAD2 and HES1. Increased vimentin expression correlated with the presence of oncogenic KRAS and with nuclear β-catenin. The corresponding liver, lymph node, brain and lung metastases did not express vimentin and displayed significantly lower levels of nuclear phospho-SMAD2 and HES1, while retaining nuclear β-catenin. Conclusions: Primary colorectal carcinomas display aberrant expression of vimentin, and have activated Notch and TGFβ signaling pathways. Surprisingly, many regional and distant metastases have lost nuclear HES1 and pSMAD2, suggesting that the activity of the Notch and TGFβ pathways is reduced in secondary colorectal tumors.
Highlights
Colorectal cancer is one of the most common malignancies in the Western world
Our study shows that the activity of the Notch and TGFβ signaling pathways which regulate epithelial homeostasis in the gut and have been implicated in colorectal cancer development are differentially active in primary colorectal tumors and their corresponding metastases
Vimentin expression in carcinomas is associated with local invasion and metastasis formation
Summary
Colorectal cancer is one of the most common malignancies in the Western world. It is well established that the development of colorectal cancer results from dysregulation of signaling pathways that normally control homeostasis in the gut, in particular those activated by the Wnt, Delta/Jagged and TGFβ ligands [1]. Mutational activation of the KRAS oncogene contributes to the initiation and/or progression of colorectal cancer [2]. These pathways do not operate as single independent entities, but extensive cross-talk and cooperation is required for tumor formation. The expression of mesenchymal (vimentin, fibronectin) and epithelial (E-cadherin) markers was related to markers of Wnt (β-catenin), Notch (HES1) and TGFβ (phospho-SMAD2) signalling. Results: When compared to normal mucosa, primary colorectal tumors showed a marked increase in the levels of cytoplasmic vimentin and nuclear β-catenin, phospho-SMAD2 and HES1. Conclusions: Primary colorectal carcinomas display aberrant expression of vimentin, and have activated Notch and TGFβ signaling pathways. Many regional and distant metastases have lost nuclear HES1 and pSMAD2, suggesting that the activity of the Notch and TGFβ pathways is reduced in secondary colorectal tumors
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