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Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden.
Microbiology and Tumour Biology Center, Karolinska Institute, Stockholm, Sweden.
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2008 (English)In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 27, no 9, 1218-1230 p.Article in journal (Refereed) Published
Abstract [en]

To better understand the dual, tumour-suppressive and tumour-promoting function of transforming growth factor-beta (TGFbeta), we analysed mammary epithelial NMuMG cells in response to short and long-term TGFbeta exposure. NMuMG cells became proliferation-arrested and apoptotic after exposure to TGFbeta for 2-5 days, whereas surviving cells underwent epithelial-mesenchymal transition (EMT). After chronic TGFbeta exposure (2-3 weeks), however, NMuMG cells became resistant to proliferation arrest and apoptosis, showing sustained EMT instead (TD cells). EMT was fully reversed by a pharmacologic TGFbeta-receptor-I kinase inhibitor or withdrawal of TGFbeta for 6-12 days. Interestingly, both cell cycle arresting/proapoptotic (Smads, p38 kinase) and antiapoptotic, proliferation and EMT-promoting signalling pathways (PI3K-PKB/Akt, ERK) were co-suppressed to low, but significant levels. Except for PI3K-Akt, TGFbeta-dependent downregulation of these signalling pathways in transdifferentiated (TD) cells was fully reversed upon TGFbeta withdrawal, together with partial re-induction of proliferation arrest and apoptosis. Co-injection of non-tumorigenic NMuMG cells with tumour-forming CHO cells oversecreting exogenous TGFbeta1 (CHO-TGFbeta1) allowed outgrowth of epithelioid cells in CHO-TGFbeta1 cell-induced tumours. These epithelial islands enhanced CHO-TGFbeta1 tumour cell proliferation, possibly due to chemokines (for example, JE/MCP-1) secreted by NMuMG/TD cells. We conclude that suppression of antiproliferative, proapoptotic TGFbeta signalling in TD cells may permit TGFbeta-dependent proliferation, survival and EMT-enhancing signalling pathways to act at low levels. Thus, TGFbeta may modulate its own signalling to facilitate switching from tumour suppression to tumour progression.

Place, publisher, year, edition, pages
2008. Vol. 27, no 9, 1218-1230 p.
Keyword [en]
epithelial–mesenchymal transition, metastasis, Smad, signal transduction, TGFb, tumour suppression
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-12869DOI: 10.1038/sj.onc.1210741ISI: 000253407000004PubMedID: 17724470OAI: oai:DiVA.org:uu-12869DiVA: diva2:40639
Available from: 2008-01-18 Created: 2008-01-18 Last updated: 2017-12-11Bibliographically approved

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Sjöblom, TobiasMoustakas, Aristidis

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