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TGF-β signaling alters the pattern of liver tumorigenesis induced by Pten inactivation

Oncogene volume 34, pages 3273–3282 (2015)Cite this article

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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 (Tgfbr2LKO) had no overt phenotype, while inactivation of Pten alone (PtenLKO), resulted in the formation of both hepatocellular carcinomas and cholangiocarcinomas (CC). Interestingly, deletion of both Pten and Tgfbr2 (PtenLKO;Tgfbr2LKO) 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 PtenLKO and PtenLKO;Tgfbr2LKO 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 (Tgfbr2LKO, PtenLKO, PtenLKO;Tgfbr2LKO) 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 PtenLKO mice and PtenLKO;Tgfbr2LKO mice is secondary to the altered regulation of stem-cell features induced by the loss of TGF-β signaling.

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Acknowledgements

This work is supported in part by funding from Burroughs Wellcome Fund, the National Institutes of Health (RO1 DK60669-01 and P30 CA015704, WMG) and by the National Institutes of Health Interdisciplinary Training Grant (T32 CA080416, SMM). The authors thank Jean Campbell and members of the Grady laboratory for helpful suggestions. We also wish to acknowledge support from the Experimental Histopathology, Scientific Imaging and Comparative Medicine Cores at the Fred Hutchinson Cancer Research Center.

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S M Morris, K T Carter, A Koszarek & W M Grady

  2. Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea

    J Y Baek

  3. Department of Pathology, University of Washington Medical School, Seattle, WA, USA

    M M Yeh

  4. Comparative Medicine, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    S E Knoblaugh

  5. Department of Medicine, University of Washington Medical School, Seattle, WA, USA

    W M Grady

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  1. S M Morris
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Correspondence to W M Grady.

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Morris, S., Carter, K., Baek, J. et al. TGF-β signaling alters the pattern of liver tumorigenesis induced by Pten inactivation. Oncogene 34, 3273–3282 (2015). https://doi.org/10.1038/onc.2014.258

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