Abstract
Background: TGF-beta plays dual roles in progression of human cancer. In precancerous stages, TGF-beta acts as tumor suppressor by providing cytostatic downstream signaling, whereas in late cancer stages, it induces processes that support tumor progression, including stroma fibroblast activation, epithelial mesenchymal transition and metastasis. Due to the high complexity of the TGF-beta signaling pathway, molecular details of this dramatic functional switch are only poorly understood. Recently, a shift from Smad2/3 C-terminal to linker site phosphorylation was hypothesized as key event for the cancer facilitating outcome of TGF-beta in colorectal and hepatocellular carcinoma. In the present study, we investigated this assumption in gastric adenocarcinoma. Methods: Immunohistochemical staining with anti-P-Smad2/3C and p-Smad2/3L antibodies was performed with 130 paraffin-embedded gastric adenocarcinoma cancer specimen. Relationship of immunohistochemical score with clinicopathologic characteristics of these patients was estimated. Results: No significant P-Smad2L and/or P-Smad3L positive staining was found in the tested samples, neither from healthy controls nor from patients with gastric adenocarcinoma, whereas loss of P-Smad2C positive staining remarkably correlates with depth of tumor and differentiation of cancer in patients with gastric cancer. P-Smad3C staining did not significantly correlate with clinicopathologic gastric adenocarcinoma characteristics. However and interestingly, IHC score of P-Smad3C is associated with a-SMA positive cancer associated fibroblasts and P-Smad3C positive staining colocalised with a-SMA and collagen I expression in cancer cells. Conclusions: Smad2/3L phosphorylation does not occur in gastric cancer. Smad2 C-terminal phosphorylation mediated signaling may have important tumor preventing activity in gastric adenocarcinoma. Smad3 activation is not directly linked to clinical gastric cancer characteristics, however may participate in tumor stroma fibroblast activation and epithelial-to-mesenchymal transition of cancer cells in gastric cancer progression and metastasis.
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