Distinct mechanisms of TGF-beta1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis
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View abstract on PubMed
Summary
This summary is machine-generated.Skin cancers often have high TGF-beta1 and low TGF-beta type II receptor (TGF-βRII). This study shows TGF-β1 drives metastasis via distinct pathways, with reduced TGF-βRII promoting invasion.
Area Of Science
- Oncology
- Molecular Biology
- Dermatology
Background
- Human skin cancers frequently overexpress TGF-beta1.
- These cancers also show decreased expression of the TGF-beta type II receptor (TGF-βRII).
- The combined effect of these molecular changes on cancer prognosis is not fully understood.
Purpose Of The Study
- To investigate the role of TGF-beta1 and TGF-βRII in skin cancer progression.
- To elucidate the mechanisms by which TGF-beta1 influences epithelial-to-mesenchymal transition (EMT) and metastasis.
- To understand how altered TGF-βRII signaling impacts TGF-beta1-driven cancer phenotypes.
Main Methods
- Generation of a transgenic mouse model with inducible TGF-beta1 expression and dominant-negative TGF-βRII (DeltaβRII) in keratinocytes.
- Induction of TGF-beta1 in late-stage, chemically induced papillomas with and without DeltaβRII expression.
- Analysis of tumor growth, metastasis, EMT markers (E-cadherin/catenin), Smad activation, RhoA/Rac, and MAPK signaling.
Main Results
- TGF-beta1 induction alone increased metastasis and EMT without inhibiting tumor growth.
- DeltaβRII expression abrogated TGF-beta1-mediated EMT and restored E-cadherin/catenin.
- TGF-beta1/DeltaβRII tumors showed increased metastasis independent of EMT, involving RhoA/Rac and MAPK pathways, despite blocked Smad activation.
Conclusions
- TGF-beta1 induces EMT through functional TGF-βRII signaling.
- TGF-beta1-mediated tumor invasion and metastasis can occur independently of EMT and Smad activation, cooperating with reduced TGF-βRII signaling.
- Distinct mechanisms mediate TGF-beta1's effects on EMT and invasion, highlighting complex roles in skin cancer progression.
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