Distinct mechanisms of TGF- 1-mediated epithelial-to-mesenchymal transition and metastasis during skin carcinogenesis

Abstract

In the present study, we demonstrated that human skin cancers frequently overexpress TGF-β 1 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-β 1 in keratinocytes expressing a dominant negative TGF-βRII (∆βRII) in the epidermis. Without ∆βRII expression, TGF-β 1 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, ∆βRII expression abrogated TGF-β 1 -mediated EMT and was accompanied by restoration of membrane-associated E-cadherin/catenin complex in TGF-β 1 /∆βRII compound tumors. Furthermore, expression of molecules thought to mediate TGF-β 1 -induced EMT was attenuated in TGF-β 1 /∆βRII-transgenic tumors. However, TGF-β 1 /∆βRII-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-β 1 -transgenic, or ∆βRII-transgenic mice. Abrogation of Smad activation by ∆βRII correlated with the blockade of EMT. However, ∆βRII did not alter TGF-β 1 -mediated expression of RhoA/Rac and MAPK, which contributed to increased metastasis. Our study provides evidence that TGF-β 1 induces EMT and invasion via distinct mechanisms. TGF-β 1 -mediated EMT requires functional TGF-βRII, whereas TGF-β 1 -mediated tumor invasion cooperates with reduced TGF-βRII signaling in tumor epithelia.

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…TGFbR2 is considered an absolute requirement for TGFb-mediated EMT program. 35 Crosstalk among MSC and melanoma cells in low pH condition is also characterized and, possibly, sustained by an elicited metabolic symbiosis. This symbiosis is based on OxPhos metabolism expressed by acidic MSC and a forced glycolytic metabolism of melanoma cells grown in LpH-MSC medium.…”

Epithelial-mesenchymal transition during extravillous trophoblast differentiation

“…22 In the early stages of cancer, TGFb acts as a growth inhibitor and tumor-suppressor; but in the later stages, it can act as a potent inducer of EMT. 23 Genetic and molecular changes in malignant cells are thought to alter their responses to signaling molecues. The loss of SMAD3 in choricarcinomas is responsible for their resistance to TGFb.…”

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

“…In addition, transforming growth factor type ␤-1 (TGF-␤) was detected in both in situ and invasive SCCs at levels that correlate with malignancy (3)(4)(5). TGF-␤ is a pleiotropic molecule acting as a potent growth suppressor on epithelial cells (6).…”