Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

doi:10.1073/pnas.0705395105

Progenitor/stem cells give rise to liver cancer due to aberrant TGF-β and IL-6 signaling

*Cancer Genetics, Digestive Diseases and Developmental Molecular Biology,
^†Institute of Transplant Surgery, Department of Surgery,
^§Lombardi Comprehensive Cancer Center, and
^‖Department of Medicine and Oncology, Georgetown University, 3900 Reservoir Road, Medical/Dental Building, Washington, DC 20007;
^‡Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Bethesda, MD 20892;
^¶Department of Pathology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030;
^§§Department of Veterans Affairs Medical Center, 50 Irving Street NW, Washington, DC 20422;
^‡‡Fels Institute for Cancer Research and Molecular Biology, Temple University, 3307 North Broad Street, Allied Health Building, Philadelphia, PA 19140; and
**Cancer Diagnosis Program, National Cancer Institute, Rockville, MD 20852

Edited by Raymond L. White, University of California, San Francisco, Emeryville, CA, and approved December 10, 2007 (received for review June 8, 2007)

Abstract

Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ “cancer stem cells,” such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000–50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-β-receptor type II (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf ^+/− mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-β signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf ^+/− mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-β signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-β pathway.

Footnotes

^††To whom correspondence may be addressed. E-mail: kirti.shetty{at}medstar.net, lynt.johnson{at}medstar.net, or lm229{at}georgetown.edu
Author contributions: Y.T. and K.K. contributed equally to this work; Y.T., K.K., K.S., J.M.J., B.M., L.J., and L.M. designed research; Y.T., K.K., W.J., C.L., C.-X.D., and J.S.M. performed research; C.L., C.-X.D., S.C.M., and H.W.R. contributed new reagents/analytic tools; Y.T., K.K., S.C.M., H.R., A.R., A.R.H., K.S., J.M.J., M.Z., B.M., E.P.R., L.J., and L.M. analyzed data; and Y.T., K.K., A.R.H., J.M.J., K.S., M.Z., B.M., E.P.R., L.J., and L.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0705395105/DC1.