Purpose of Study Transforming growth factor β (TGF-β) has roles in both tumor suppression and promotion. Although Smad2 and Smad3 are TGF-β signaling mediators, their functions in mediating TGF-β signaling during cancer development remain to be determined. We have examined expression patterns of Smad2 and Smad3 in human skin SCCs and found that over 95% of tumor samples retain Smad3, whereas 70% of SCCs have lost the Smad2 protein. Previously, we have shown that Smad3 knockout mice are resistant to skin carcinogenesis due to abrogation of TGF-β-mediated tumor promotion effect.
Methods Used In the current study, we assessed the role of Smad2 in skin carcinogenesis by generating mice with keratinocyte-specific Smad2 deletion.
Summary of Results Although conditional Smad2 knockout mice did not develop spontaneous skin tumors, when exposed to a two-stage chemical carcinogenesis protocol, they exhibited accelerated tumor formation and malignant progression compared with wild-type mice. Smad2−/− tumors were more poorly differentiated in comparison with tumors from wild-type mice. At the papilloma stage, Smad2−/− tumors exhibited molecular alterations usually associated with late-stage SCC progression and epithelial-mesenchymal transition (EMT), eg, a significant elevation of keratin K8, snail, twist, tenascin C and vimentin. Additionally, Smad2−/− tumors displayed HGF-dependent vessel growth culminating in approximately three times the angiogenesis seen in Smad2+/+ tumors. Since these molecules are documented or potential TGF-β target genes, we examined TGF-β1 levels in Smad2−/− tumors. We found that neither the TGF-β1 level nor Smad3 activation was elevated in Smad2−/− tumors.
Conclusions Reached Thus, our study suggests that Smad2 loss results in the elevation of tumor invasion-associated and angiogenesis genes via a TGF-β-independent mechanism.
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