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TGF-β signaling alters the pattern of liver tumorigenesis induced by Pten inactivation
S M Morris1, K T Carter1, J Y Baek2
1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Abstract:
Hepatocarcinogenesis results from the accumulation of genetic and epigenetic changes in liver cells. A common mechanism through which these alterations induce liver cancer is by deregulating signaling pathways. A number of signaling pathways, including the PI3K/PTEN/AKT and transforming growth factor β (TGF-β) pathways have been implicated in normal liver development as well as in cancer formation. In this study, we assessed the effect of the TGF-β signaling pathway on liver tumors induced by phosphatase and tensin homolog (Pten) loss. Inactivation of only the TGF-β receptor type II, Tgfbr2, in the mouse liver (Tgfbr2(LKO)) had no overt phenotype, while inactivation of Pten alone (Pten(LKO)), resulted in the formation of both hepatocellular carcinomas and cholangiocarcinomas (CC). Interestingly, deletion of both Pten and Tgfbr2 (Pten(LKO);Tgfbr2(LKO)) in the mouse liver resulted in a dramatic shift in tumor type to predominantly CC. Assessment of the PI3K/PTEN/AKT pathway revealed increased phosphorylation of AKT and glycogen synthase kinase 3 beta (GSK-3β) in both the Pten(LKO) and Pten(LKO);Tgfbr2(LKO) mice, suggesting that this pathway is constitutively active regardless of the status of the TGF-β signaling pathway. However, phosphorylation of p70 S6 kinase was observed in the liver of all three phenotypes (Tgfbr2(LKO), Pten(LKO), Pten(LKO);Tgfbr2(LKO)) indicating that the loss of Tgfbr2 and/or Pten leads to an increase in this signaling pathway. Analysis of markers of liver progenitor/stem cells revealed that the loss of TGF-β signaling resulted in increased expression of c-Kit and CD133. Furthermore, in addition to increased c-Kit and CD133, Scf and EpCam expression were also increased in the double knock-out mice. These results suggest that the alteration in tumor types between the Pten(LKO) mice and Pten(LKO);Tgfbr2(LKO) mice is secondary to the altered regulation of stem-cell features induced by the loss of TGF-β signaling.
Insights
Loss of transforming growth factor beta (TGF-β) signaling in mice with phosphatase and tensin homolog (Pten) loss promotes cholangiocarcinoma by increasing stem cell markers. This highlights TGF-β
Area of Science:
- Hepatology
- Molecular Biology
- Cancer Research
Background:
- Hepatocarcinogenesis involves genetic and epigenetic changes that deregulate signaling pathways.
- The PI3K/PTEN/AKT and TGF-β pathways are crucial in liver development and cancer.
- Understanding pathway interactions is key to deciphering liver cancer mechanisms.
Purpose of the Study:
- To investigate the impact of the TGF-β signaling pathway on liver tumors induced by Pten loss.
- To analyze how combined Pten and Tgfbr2 inactivation affects tumor type and signaling.
- To explore the role of TGF-β signaling in regulating liver progenitor/stem cell markers.
Main Methods:
- Generated genetically modified mice with liver-specific inactivation of Tgfbr2, Pten, or both.
- Assessed tumor types (hepatocellular carcinoma and cholangiocarcinoma) in the generated mouse models.
- Analyzed key signaling pathway components (AKT, GSK-3β, p70 S6 kinase) and stem cell markers (c-Kit, CD133, Scf, EpCam) via molecular assays.
Main Results:
- Pten loss induced both hepatocellular carcinomas and cholangiocarcinomas; Tgfbr2 loss alone had no phenotype.
- Combined Pten and Tgfbr2 loss dramatically shifted tumor profiles towards predominantly cholangiocarcinomas.
- Loss of TGF-β signaling increased expression of stem cell markers c-Kit, CD133, Scf, and EpCam.
Conclusions:
- The PI3K/PTEN/AKT pathway is constitutively active in Pten-deficient liver tumors.
- Loss of TGF-β signaling, in conjunction with Pten loss, promotes cholangiocarcinoma development.
- Altered tumor types are linked to TGF-β signaling's regulation of stem cell features in the liver.
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