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Distinct mechanisms of TGF-β1–mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis
Gangwen Han, … , Molly Kulesz-Martin, Xiao-Jing Wang
Gangwen Han, … , Molly Kulesz-Martin, Xiao-Jing Wang
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1714-1723. https://doi.org/10.1172/JCI24399.
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Research Article Oncology

Distinct mechanisms of TGF-β1–mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

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Abstract

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β1 but exhibit decreased expression of the TGF-β type II receptor (TGF-βRII). To understand how this combination affects cancer prognosis, we generated a transgenic mouse model that allowed inducible expression of TGF-β1 in keratinocytes expressing a dominant negative TGF-βRII (ΔβRII) in the epidermis. Without ΔβRII expression, TGF-β1 transgene induction in late-stage, chemically induced papillomas failed to inhibit tumor growth but increased metastasis and epithelial-to-mesenchymal transition (EMT), i.e., formation of spindle cell carcinomas. Interestingly, ΔβRII expression abrogated TGF-β1–mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β1/ΔβRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β1–induced EMT was attenuated in TGF-β1/ΔβRII–transgenic tumors. However, TGF-β1/ΔβRII–transgenic tumors progressed to metastasis without losing expression of the membrane-associated E-cadherin/catenin complex and at a rate higher than those observed in nontransgenic, TGF-β1–transgenic, or ΔβRII-transgenic mice. Abrogation of Smad activation by ΔβRII correlated with the blockade of EMT. However, ΔβRII did not alter TGF-β1–mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β1 induces EMT and invasion via distinct mechanisms. TGF-β1–mediated EMT requires functional TGF-βRII, whereas TGF-β1–mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

Authors

Gangwen Han, Shi-Long Lu, Allen G. Li, Wei He, Christopher L. Corless, Molly Kulesz-Martin, Xiao-Jing Wang

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Figure 7

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Angiogenesis and proteinase expression. (A) CD31 immunofluorescence. CD3...
Angiogenesis and proteinase expression. (A) CD31 immunofluorescence. CD31 (green) highlights vessels. K14 (red) highlights the epithelial portion of tumors. Scale bar: 75 μm for all panels. (B) Percentage of the stromal area covered by vessels in TGF-β1/ΔβRII–, TGF-β1–, and ΔβRII-transgenic and control SCCs. The numbers in parentheses represents the number of tumors examined from each group. *P < 0.05. (C and D) Expression levels of VEGFR1 and VEGF (C) and MMP-2 and MMP-9 (D) detected by RPA in SCCs from TGF-β1–, ΔβRII-, and TGF-β1/ΔβRII–transgenic and control mice 25 weeks after DMBA initiation. L32 (C) or cyclophilin (Cyc.; D) was used to normalize the amount of RNA loaded in each lane.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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