Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness
- PMID: 11884518
- DOI: 10.1242/jcs.115.6.1189
Hepatocytes convert to a fibroblastoid phenotype through the cooperation of TGF-beta1 and Ha-Ras: steps towards invasiveness
Abstract
In hepatocarcinogenesis, it is an open question whether transforming growth factor (TGF)-beta1 provides a tumor-suppressive or a tumor-promoting role. To address this question, we employed immortalized murine hepatocytes, which display a high degree of differentiation and, expectedly, arrest in the G1 phase under exposure to TGF-beta1. These hepatocytes maintain epithelial polarization upon expression of oncogenic Ha-Ras. However, Ras-transformed hepatocytes rapidly convert to a spindle-shaped, fibroblastoid morphology upon treatment with TGF-beta1, which no longer inhibits proliferation. This epithelial to fibroblastoid conversion (EFC) is accompanied by disruption of intercellular contacts and remodeling of the cytoskeletal framework. Fibroblastoid derivatives form elongated branching cords in collagen gels and grow to severely vascularized tumors in vivo, indicating their increased malignancy and even invasive phenotype. Additionally, fibroblastoid cells secrete strongly enhanced levels of TGF-beta1, suggesting an autocrine regulation of TGF-beta signaling. Expression profiling further revealed that the loss of the adhesion component E-cadherin correlates with the upregulation of its transcriptional repressor Snail in fibroblastoid cells. Moreover, the phosphoinositide 3-OH (PI3) kinase pathway was required for the maintenance of EFC, as inhibition of PI3 kinase reverted fibroblastoid cells to an epithelial-like phenotype. Taken together, these data indicate a dual role of TGF-beta1 in hepatocytes: it induces proliferation arrest but provides a crucial function in promoting late malignant events in collaboration with activated Ha-Ras.
Similar articles
-
Transforming growth factor-beta1 promotes invasiveness after cellular transformation with activated Ras in intestinal epithelial cells.Exp Cell Res. 2001 Jun 10;266(2):239-49. doi: 10.1006/excr.2000.5229. Exp Cell Res. 2001. PMID: 11399052
-
TGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cells.Genes Dev. 1996 Oct 1;10(19):2462-77. doi: 10.1101/gad.10.19.2462. Genes Dev. 1996. PMID: 8843198
-
Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation.Cancer Res. 2001 May 15;61(10):4222-8. Cancer Res. 2001. PMID: 11358848
-
Transforming growth factor-beta and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes.J Cell Sci. 2002 Nov 15;115(Pt 22):4227-36. doi: 10.1242/jcs.00091. J Cell Sci. 2002. PMID: 12376555
-
Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions.J Biol Chem. 2003 Jun 6;278(23):21113-23. doi: 10.1074/jbc.M211304200. Epub 2003 Mar 28. J Biol Chem. 2003. PMID: 12665527
Cited by
-
Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer.Am J Pathol. 2002 Nov;161(5):1881-91. doi: 10.1016/S0002-9440(10)64464-1. Am J Pathol. 2002. PMID: 12414534 Free PMC article.
-
Endothelial-mesenchymal transition in bleomycin-induced pulmonary fibrosis.Am J Respir Cell Mol Biol. 2010 Aug;43(2):161-72. doi: 10.1165/rcmb.2009-0031OC. Epub 2009 Sep 18. Am J Respir Cell Mol Biol. 2010. PMID: 19767450 Free PMC article.
-
KLF4 prevents epithelial to mesenchymal transition in human corneal epithelial cells via endogenous TGF-β2 suppression.Regen Ther. 2019 Sep 12;11:249-257. doi: 10.1016/j.reth.2019.08.003. eCollection 2019 Dec. Regen Ther. 2019. PMID: 31538102 Free PMC article.
-
Tetraspanin in oncogenic epithelial-mesenchymal transition.J Clin Invest. 2008 Apr;118(4):1347-50. doi: 10.1172/JCI35308. J Clin Invest. 2008. PMID: 18357345 Free PMC article.
-
Epithelial-mesenchymal transition in hepatocellular carcinoma.Future Oncol. 2009 Oct;5(8):1169-79. doi: 10.2217/fon.09.91. Future Oncol. 2009. PMID: 19852728 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials